Antibacterial piperdine derivatives

ABSTRACT

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.

This application is a US National Stage under 35 U.S.C. §371 of International Application No. PCT/GB2006/000529 filed 16 Feb. 2006, the text of which is hereby incorporated by reference, which claims priority under 35 U.S.C. §119(e) to Application No. 60/654,670 filed on 18 Feb. 2005.

BACKGROUND OF THE INVENTION

The present invention relates to compounds which demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium.

The preferred clinically effective antibiotic for treatment of last resort of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with various toxicities, including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as β-lactams, quinolones and macrolides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H. influenzae and M. catarrhalis.

Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.

Deoxyribonucleic acid (DNA) gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, J. J.; 2001. Ann. Rev. Biochem. 70: 369-413). Type II topoisomerases use the free energy from adenosine triphosphate (ATP) hydrolysis to alter the topology of DNA by introducing transient double-stranded breaks in the DNA, catalyzing strand passage through the break and resealing the DNA. DNA gyrase is an essential and conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA. The enzyme consists of two subunits, encoded by gyrA and gyrB, forming an A₂B₂ tetrameric complex. The A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage. The B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.

Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV; as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).

DNA gyrase is a well-validated target of antibacterials, including the quinolones and the coumarins. The quinolones (e.g. ciprofloxacin) are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol. Rev. 61: 377-392). Members of this class of antibacterials also inhibit topoisomerase IV and as a result, the primary target of these compounds varies among species. Although the quinolones are successful antibacterials, resistance generated primarily by mutations in the target (DNA gyrase and topoisomerase IV) is becoming an increasing problem in several organisms, including S. aureus and Streptococcus pneumoniae (Hooper, D. C., 2002, The Lancet Infectious Diseases 2: 530-538). In addition, quinolones, as a chemical class, suffer from toxic side effects, including arthropathy that prevents their use in children (Lipsky, B. A. and Baker, C. A., 1999, Clin. Infect. Dis. 28: 352-364). Furthermore, the potential for cardiotoxicity, as predicted by prolongation of the QT_(c) interval, has been cited as a toxicity concern for quinolones.

There are several known natural product inhibitors of DNA gyrase that compete with ATP for binding the GyrB subunit (Maxwell, A. and Lawson, D. M. 2003, Curr. Topics in Med. Chem. 3: 283-303). The coumarins are natural products isolated from Streptomyces spp., examples of which are novobiocin, chlorobiocin and coumermycin A1. Although these compounds are potent inhibitors of DNA gyrase, their therapeutic utility is limited due to toxicity in eukaryotes and poor penetration in Gram-negative bacteria (Maxwell, A. 1997, Trends Microbiol. 5: 102-109). Another natural product class of compounds that targets the GyrB subunit is the cyclothialidines, which are isolated from Streptomyces filipensis (Watanabe, J. et al 1994, J. Antibiot. 47: 32-36). Despite potent activity against DNA gyrase, cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).

Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomerase IV are known in the art. For example, coumarin-containing compounds are described in patent application number WO 99/35155, 5,6-bicyclic heteroaromatic compounds are described in patent application WO 02/060879, and pyrazole compounds are described in patent application WO 01/52845 (U.S. Pat. No. 6,608,087).

We have discovered a new class of compounds which are useful for inhibiting DNA gyrase and topoisomerase IV.

SUMMARY OF THE INVENTION

Therefore the present invention provides a compound of formula (I):

wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

W is —O—, —N(R⁶)— or —C(R⁷)(R⁸)—;

X is a direct bond, —CH₂—, —C(O)— or S(O)_(q)— (wherein q is 1 or 2);

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, C₁₋₄alkoxyiminomethyl, N-hydroxyformamido, C₁₋₄hydrazino, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

n is 1-4; wherein the values of R⁴ may be the same or different;

m is 0-4; wherein the values of R⁵ may be the same or different;

R¹² is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁ ₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula (IA):

wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl; R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl; X is a direct bond, —CH₂—, —C(O)— or S(O)_(q)— (wherein q is 1 or 2);

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamido, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂ ₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

n is 1-4; wherein the values of R⁴ may be the same or different;

m is 0-4; wherein the values of R⁵ may be the same or different;

R¹² is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁ ₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula (IB):

wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamido, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂ ₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

n is 1-4; wherein the values of R⁴ may be the same or different;

m is 0-4; wherein the values of R⁵ may be the same or different;

R¹² is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁ ₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula (IC):

wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamido, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂ ₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

m is 0-4; wherein the values of R⁵ may be the same or different;

R¹² is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁ ₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula (IC):

wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

Ring A is heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamido, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

m is 0-4; wherein the values of R⁵ may be the same or different;

R¹² is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula (IE):

wherein: Y is NH, N(C₁₋₄alkyl) or S;

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

X is a direct bond, —CH₂—, —C(O)— or S(O)_(q)— (wherein q is 1 or 2);

Ring A is heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ is a substitutent on carbon selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamido, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R^(5a) and R^(5b) are substituents as defined for R⁴ or taken together with the carbons to which they are attached form a 6-membered carbocyclyl ring substituted by one or two groups which may be the same or different and which are selected from R⁵;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

R¹² is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of formula (IF):

wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, —C═N—OR′ wherein R′ is H or C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2 and C₃₋₆cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C₃₋₆cycloalkyl;

X is a direct bond, —CH₂—, —C(O)— or S(O)_(q)— (wherein q is 1 or 2);

R⁴ is a substitutent on carbon selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, N-hydroxyformamido, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—(C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R^(5a) and R^(5b) are substituents as defined for R⁴ or taken together with the carbons to which they are attached form a 6-membered carbocyclyl ring substituted by one or two groups which may be the same or different and which are selected from R⁵;

R⁶, R⁷ and R⁸ are independently selected from hydrogen or C₁₋₄alkyl;

R¹² is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound which is

-   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[(1S)-2-methoxy-1-methylethyl]amino}carbonyl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-O-4-[(methylamino)carbonyl]-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic     acid; -   4-acetyl-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[(1R)-2-methoxy-1-methylethyl]amino}carbonyl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[(2S)-2-methoxypropyl]amino}carbonyl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[(2R)-2-methoxypropyl]amino}carbonyl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[(1R,2S)-2-fluorocyclopropyl]amino}carbonyl)-1,3-thiazole-5-carboxylic     acid; -   Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylic     acid; -   Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylic     acid; -   Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinic     acid; -   2-((3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylic     acid; -   Cis(±)-2-(3-chloro-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylic     acid; -   2-((3S,4R)-4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic     acid; -   Cis(±)-2-[4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-yn-1-yloxy)piperidin-1-yl]-1,3-thiazole-5-carboxylic     acid; -   Cis(±)2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-4-carboxylic     acid; or -   2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[2-methoxy-1-(methoxymethyl)ethyl]amino}carbonyl)-1,3-thiazole-5-carboxylic     acid;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition that comprises a compound of formula I, IA, IB, IC, or IE or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.

The invention also provides a method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula I, IA, IB, IC, or IE, or a pharmaceutically-acceptable salt thereof.

The invention also provides a method for inhibiting bacterial DNA gyrase in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, IA, IB, IC, or IE or a pharmaceutically acceptable salt.

The invention also provides a compound of formula I, IA, IB, IC, or IE and pharmaceutically acceptable salts thereof for use as a medicament.

The invention also provides the use of a compound of formula I, IA, IB, IC, or IE, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.

The invention also provides the use of a compound of formula I, IA, IB, IC, or IE, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.

The present invention also provides a process for preparing compounds of formula (I) or pharmaceutically-acceptable salts thereof, comprising:

Process a) for compounds of formula (I) wherein W is —C(R⁷)(R⁸)—; converting a compound of formula (II):

wherein R^(a) is cyano and R^(b) is dimethyamino or diethylamino; or R^(a) and R^(b) are independently selected from C₁₋₄alkylthio; or R^(a) and R^(b) together form 1,3-dithianyl or 1,3-dithiolanyl; into a compound of formula (I); Process b) for compounds of formula (I) wherein W is —O—; reacting a compound of formula (III):

with a compound of formula (IV):

Process c) for compounds of formula (I) wherein W is —N(R⁶)—; reacting a compound of formula (V):

with a compound of formula (IV) or an activated acid derivative thereof; Process d) for compounds of formula (I) wherein W is —C(R⁷)(R⁸)—; reacting a compound of formula (VI):

wherein L is a displaceable group; with a compound of formula (VII):

Process e) for compounds of formula (I) wherein W is —C(R⁷)(R⁸)—; reacting a compound of formula (VIII):

wherein M is an organometallic group; with a compound of formula (IX):

wherein L is a displaceable group; Process f) reacting a compound of formula (X):

with a compound of formula (XI):

wherein D is a displaceable group; Process g) for compounds of formula (I) wherein X is —C(O)—; reacting a compound of formula (X) with a compound of formula (XII):

and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of     the formula (I); -   ii) removing any protecting groups; -   iii) forming a pharmaceutically acceptable salt.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In this specification the term alkyl includes both straight and branched chain alkyl groups. For example, “C₁₋₄alkyl” includes methyl, ethyl, propyl, isopropyl and t-butyl. However references to individual alkyl groups such as propyl are specific for the straight chain version only. An analogous convention applies to other generic terms.

Where optional substituents are chosen from one or more groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH₂-group can optionally be replaced by a —C(O)— and a ring nitrogen and/or a ring sulphur atom may be optionally oxidised to form the N- or S-oxide(s). In one aspect of the invention a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a —CH₂— group can optionally be replaced by a —C(O)— and a ring sulphur atom may be optionally oxidised to form the S-oxides. In a further aspect of the invention a “heterocyclyl” is an unsaturated, carbon-linked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen. Examples and suitable values of the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. Further examples and suitable values of the term “heterocyclyl” are thiazolyl, quinolinyl, benzothiazolyl, pyrimidinyl and pyridinyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— group can optionally be replaced by a —C(O)—. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. A particular example of “carbocyclyl” is phenyl.

An example of “C₁₋₄alkanoyloxy” is acetoxy. Examples of “C₁₋₄alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C₁₋₄alkoxycarbonylamino” include methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino Examples of “C₁₋₄alkoxy” include methoxy, ethoxy and propoxy. Examples of “C₁₋₄alkanoylamino” include formamido, acetamido and propionylamino Examples of “C₁₋₄alkylS(O)_(a) wherein a is 0 to 2” include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C₁₋₄alkanoyl” include propionyl and acetyl. Examples of “N—(C₁₋₄alkyl)amino” include methylamino and ethylamino Examples of “N,N—(C₁₋₄alkyl)₂amino” include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino Examples of “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl. Examples of “C₂₋₄alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of “N—(C₁₋₄alkyl)sulphamoyl” are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of “N,N—(C₁₋₄alkyl)₂sulphamoyl” are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of “N—(C₁₋₄alkyl)carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl. Examples of “N,N—(C₁₋₄alkyl)₂carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “N—(C₁₋₄alkoxy)carbamoyl” are methoxyaminocarbonyl and isopropoxyaminocarbonyl. Examples of “N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl” are N-methyl-N-methoxyaminocarbonyl and N-methyl-N-ethoxyaminocarbonyl. Examples of “C₃₋₆cycloalkyl” are cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl. Examples of “N′—(C₁₋₄alkyl)ureido” are N′-methylureido and N′-isopropylureido. Examples of “N′,N′—(C₁₋₄alkyl)₂ureido” are N′N′-dimethylureido and N′-methyl-N′-isopropylureido. Examples of “N′—(C₁₋₄alkyl)hydrazinocarbonyl” are N′-methylhydrazinocarbonyl and N′-isopropylhydrazinocarbonyl. Examples of “N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl” are N′N′-dimethylhydrazinocarbonyl and N′-methyl-N′-isopropylhydrazinocarbonyl. Examples of “C₁₋₄alkylsulphonylamino” include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino Examples of “C₁₋₄alkylsulphonylaminocarbonyl” include methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-butylsulphonylaminocarbonyl. Examples of “C₁₋₄alkylsulphonyl” include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.

A compound of formula (I) may form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, tromethamine, N-methyl d-glucamine and amino acids such as glycine or lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.

Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits DNA gyrase and/or topoisomeraseIV and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. The same applies to compound names. It will be appreciated by those skilled in the art that certain compounds of formula (I) contain an asymmetrically substituted carbon and/or sulphur atom, and accordingly may exist in, and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the inhibition of DNA gyrase and/or topoisomeraseIV, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the inhibition of DNA gyrase and/or topoisomeraseIV by the standard tests described hereinafter.

It is also to be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit DNA gyrase and/or topoisomeraseIV.

Particular and suitable values for certain substituents and groups referred to in this specification are listed below. These values may be used where appropriate with any of the definitions and embodiments disclosed herein. Each stated species represents a particular and independent aspect of the invention.

Referring to a compound of formula I, R¹ is C₁₋₄alkyl. R¹ is methyl. R¹ is halo. R¹ is hydrogen.

R² is methyl. R² is halo. R² is fluoro or chloro. R² is hydrogen. R² is chloro.

R³ is C₁₋₄alkyl. R³ is methyl. R³ is halo. R³ is fluoro or chloro. R³ is hydrogen. R³ is CN. R³ is C═N—OH. R³ is chloro.

W is —O—. W is —N(R⁶)—. W is —NH—. W is —C(R⁷)(R⁸)—.

X is a direct bond. X is —CH₂—. X is —C(O)—. X is S(O)_(q)— (wherein q is 1 or 2).

Ring A is carbocyclyl. Ring A is heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹. Ring A is heterocyclyl. Ring A is thiazolyl, quinolinyl, benzothiazolyl, pyrimidinyl or pyridinyl. Ring A is thiazol-2-yl, quinolin-4-yl, benzothiazol-2-yl, pyrimidin-4-yl, pyridin-2-yl or pyridin-4-yl.

R⁴ is a substituent on carbon and is selected from halo, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkoxycarbonyl or heterocyclyl-R¹¹—; wherein R⁴ may be optionally substituted on carbon by one or more R¹². R¹² is selected from hydroxy, C₂₋₄alkenyl, C₁₋₄alkoxy, N—(C₁₋₄alkyl)amino or N,N—(C₁₋₄alkyl)₂amino; and R¹¹ is —C(O)—.

Alternatively, R⁴ is a substituent on carbon and is selected from fluoro, hydroxy, carboxy, methyl, methoxy, propoxy, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-methyl-N-methoxycarbamoyl, methoxycarbonyl or morpholino-R¹¹—; wherein R⁴ may be optionally substituted on carbon by one or more R¹². R¹² is selected from hydroxy, ethenyl, methoxy, N-methylamino or N,N-dimethylamino; and R¹¹ is —C(O)—.

Alternatively, R⁴ is a substituent on carbon and is selected from methoxy, hydroxy, methoxycarbonyl, fluoro, allyloxy, propoxy, N,N-dimethylcarbamoyl, morpholinocarbonyl, N-ethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, dimethylaminomethyl, N-methyl-N-methoxycarbamoyl, methoxymethyl, methylaminomethyl and carboxy.

Alternatively, R⁴ is a substituent on carbon and is selected from methoxy, hydroxy, methoxycarbonyl, fluoro, allyloxy, propoxy, N,N-dimethylcarbamoyl, morpholinocarbonyl, N-ethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, dimethylaminomethyl, N-methyl-N-methoxycarbamoyl, methoxymethyl, methylaminomethyl, carboxy, N-methyl-N-methoxycarbamoyl, N-hydroxyethylcarbamoyl, hydroxymethyl, (methylthio)methyl, (methylsulfinyl)methyl, (methylsulfonyl)methyl, benzyloxy, propynyloxy, methoxyethoxy, methoxypropoxy, chloro, methyl, cyclopropylmethoxy, thiazolylmethoxy, ethoxy, oxyacetic acid, ethylaminocarbonyloxy, allylaminocarbonyloxy, pyridinylmethoxy, hydroxypropoxy, methoxy(methyl)amino, and azido.

Alternatively R⁴ is halo, particularly fluoro.

R⁵ is a substituent on carbon and is selected from halo, carboxy, carbamoyl, C₁₋₄alkyl, C₁₋₄alkoxy, N—(C₁₋₄alkyl)carbamoyl, N—(C₁₋₄alkoxy)carbamoyl or C₁₋₄alkoxycarbonyl; wherein R⁵ may be optionally substituted on carbon by one or more R¹². R¹² is selected from C₁₋₄alkoxy or carbocyclyl-R¹⁴—; and R¹⁴ is a direct bond.

Alternatively, R⁵ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, methyl, methoxy, N-(isopropyl)carbamoyl, N-(methoxy)carbamoyl, methoxycarbonyl or ethoxycarbonyl; wherein R⁵ may be optionally substituted on carbon by one or more R¹². R¹² is selected from methoxy or phenyl-R¹⁴—; and R¹⁴ is a direct bond.

Alternatively, R⁵ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, methyl, methoxymethyl, methoxy, N-(1-methyl-1-phenylethyl)carbamoyl, N-(methoxy)carbamoyl, methoxycarbonyl or ethoxycarbonyl.

Alternatively, R⁵ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, methyl, methoxymethyl, methoxy, N-(1-methyl-1-phenylethyl)carbamoyl, N-(methoxy)carbamoyl, methoxycarbonyl or ethoxycarbonyl, N-methoxycarbamoyl, formyl, (methoxyimino)methyl, isopropoxycarbonyl, ethoxy, morpholinocarbonyl, hydroxy-1-methylethyl, amino, methoxycarbonylamino, methylsulfonylamino, N-(1-methyl-1-phenylethyl)carbamoyl, N-2-morpholin-4-ylethylcarbamoyl, piperidinocarbonyl, N-methylcarbamoyl, N-2-hydroxyethylcarbamoyl, N-2-methoxyethylcarbamoyl, N-2-hydroxypropylcarbamoyl, N-2-hydroxy-1-methylethylcarbamoyl, N-isoxazolylcarbamoyl, N-2,2-difluoroethylcarbamoyl, N-tetrahydrofuran-3-ylcarbamoyl, N-cyclopropylcarbamoyl, N-1-cyanocyclopropylcarbamoyl, N-2-fluorocyclopropylcarbamoyl, N-2-hydroxy-1,1-dimethylethylcarbamoyl, N-1-cyano-1-methylethylcarbamoyl, N-1-(hydroxymethyl-2-methoxy-2-oxoethylcarbamoyl, N-1,3-dioxolan-2-ylmethylcarbamoyl, N-3-(2-oxopyrrolidin-1-ylpropylcarbamoyl, N-pyridin-2-ylmethylcarbamoyl, N-2-(methylthio)ethylcarbamoyl, N-1,3-oxazol-2-ylmethylcarbamoyl, N-2-fluoroethylcarbamoyl, N-(2-hydroxy-2-methylpropyl)carbamoyl, morpholin-4-ylmethyl, tert-butylaminomethyl, piperidine-1-ylmethyl, (3-hydroxypyrrolidin-1-yl)methyl, (hydroxyimino)methyl, 1,1-difluoromethyl, azidomethyl, cyano(morpholin-4-yl)methyl, N-2-(methylsulfonyl)ethylcarbamoyl, cyano, 1-hydroxy-1-methylethyl, cyclopropylmethyl, N-methylcarbamoyl, N-1-carboxycycloproylcarbamoyl, N-isoxazol-3-ylcarbamoyl, N-prop-2-yn-1 ylcarbamoyl, N-1-carboxy-2-hydroxymethylcarbamoyl, N-[3-(2-oxopyrrolidin-1-yl)propyl]carbamoyl, N-(2-hydroxy-2-methylpropyl)carbamoyl, N-methoxy-N-methylcarbamoyl, N-2-(methylsulfonyl)ethylcarbamoyl, N-methoxypropylcarbamoyl, and methoxymethyl)ethyl]amino}carbamoyl.

Alternatively R⁵ is carboxy.

R⁶ is hydrogen.

n is 1.

m is 1 or 2; wherein the values of R⁵ may be the same or different. m is 1. m is 2.

In a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R¹ is selected from C₁₋₄alkyl;

R² is selected from halo.

R³ is selected from hydrogen or halo;

W is —N(R⁶)—;

X is a direct bond;

Ring A is heterocyclyl;

R⁴ is a substituent on carbon and is selected from halo, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkoxycarbonyl or heterocyclyl-R¹¹—; wherein R⁴ may be optionally substituted on carbon by one or more R¹²;

R⁵ is a substituent on carbon and is selected from halo, carboxy, carbamoyl, C₁₋₄alkyl, C₁₋₄alkoxy, N—(C₁₋₄alkyl)carbamoyl, N—(C₁₋₄alkoxy)carbamoyl or C₁₋₄alkoxycarbonyl; wherein R⁵ may be optionally substituted on carbon by one or more R¹²;

R⁶ is hydrogen;

R¹¹ is —C(O)—;

R¹² is selected from hydroxy, C₂₋₄alkenyl, C₁₋₄alkoxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino or carbocyclyl-R¹⁴—;

R¹⁴ is a direct bond;

n is 1; and

m is 1 or 2; wherein the values of R⁵ may be the same or different;

or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R¹ is selected from methyl;

R² is fluoro or chloro;

R³ is selected from hydrogen, fluoro or chloro;

W is —NH—;

X is a direct bond;

Ring A is thiazolyl, quinolinyl, benzothiazolyl, pyrimidinyl or pyridinyl;

R⁴ is a substituent on carbon and is selected from methoxy, hydroxy, methoxycarbonyl, fluoro, allyloxy, propoxy, N,N-dimethylcarbamoyl, morpholinocarbonyl, N-ethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, dimethylaminomethyl, N-methyl-N-methoxycarbamoyl, methoxymethyl, methylaminomethyl and carboxy;

R⁵ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, methyl, methoxymethyl, methoxy, N-(1-methyl-1-phenylethyl)carbamoyl, N-(methoxy)carbamoyl, methoxymethyl)ethyl]amino}carbamoyl, methoxycarbonyl or ethoxycarbonyl;

n is 1; and

m is 1 or 2; wherein the values of R⁵ may be the same or different; or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R¹ is selected from hydrogen or methyl;

R² is hydrogen, bromo, fluoro, chloro, CN, or —C═NOMe;

R³ is selected from hydrogen, fluoro or chloro;

W is —NH—;

X is a direct bond;

Ring A is thiazolyl, quinolinyl, benzothiazolyl, pyrimidinyl or pyridinyl;

R⁴ is a substituent on carbon and is selected from methoxy, hydroxy, methoxycarbonyl, fluoro, allyloxy, propoxy, N,N-dimethylcarbamoyl, morpholinocarbonyl, N-ethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, dimethylaminomethyl, N-methyl-N-methoxycarbamoyl, methoxymethyl, methylaminomethyl, carboxy, N-methyl-N-methoxyxcarbamoyl, N-hydroxyethylcarbamoyl, hydroxymethyl, (methylthio)methyl, (methylsulfinyl)methyl, (methylsulfonyl)methyl, benzyloxy, propynyloxy, methoxyethoxy, methoxypropoxy, chloro, methyl, cyclopropylmethoxy, thiazolylmethoxy, ethoxy, oxyacetic acid, ethylaminocarbonyloxy, allylaminocarbonyloxy, pyridinylmethoxy, hydroxypropoxy, methoxy(methyl)amino, and azido;

R⁵ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, methyl, methoxymethyl, methoxy, N-(1-methyl-1-phenylethyl)carbamoyl, N-(methoxy)carbamoyl, methoxycarbonyl or ethoxycarbonyl, N-methoxycarbamoyl, formyl, (methoxyimino)methyl, isopropoxycarbonyl, ethoxy, morpholinocarbonyl, hydroxy-1-methylethyl, amino, methoxycarbonylamino, methylsulfonylamino, N-(1-methyl-1-phenylethyl)carbamoyl, N-2-morpholin-4-ylethylcarbamoyl, piperidinocarbonyl, N-methylcarbamoyl, N-2-hydroxyethylcarbamoyl, N-2-methoxyethylcarbamoyl, N-2-hydroxypropylcarbamoyl, N-2-hydroxy-1-methylethylcarbamoyl, N-isoxazolylcarbamoyl, N2,2-difluoroethylcarbamoyl, N-tetrahydrofuran-3-ylcarbamoyl, N-cyclopropylcarbamoyl, N-1-cyanocyclopropylcarbamoyl, N-2-fluorocyclopropylcarbamoyl, N-2-hydroxy-1,1-dimethylethylcarbamoyl, N-1-cyano-1-methylethylcarbamoyl, N-1-(hydroxymethyl-2-methoxy-2-oxoethylcarbamoyl, N-1,3-dioxolan-2-ylmethylcarbamoyl, N-3-(2-oxopyrrolidin-1-ylpropylcarbamoyl, N-pyridin-2-ylmethylcarbamoyl, N-2-(methylthio)ethylcarbamoyl, N-1,3-oxazol-2-ylmethylcarbamoyl, N-2-fluoroethylcarbamoyl, N-(2-hydroxy-2-methylpropyl)carbamoyl, morpholin-4-ylmethyl, tert-butylaminomethyl, piperidine-1-ylmethyl, (3-hydroxypyrrolidin-1-yl)methyl, (hydroxyimino)methyl, 1,1-difluoromethyl, azidomethyl, cyano(morpholin-4-yl)methyl, N-2-(methylsulfonyl)ethylcarbamoyl, cyano, 1-hydroxy-1-methylethyl, cyclopropylmethyl, N-methylcarbamoyl, N-1-carboxycycloproylcarbamoyl, N-isoxazol-3-ylcarbamoyl, N-prop-2-yn-1 ylcarbamoyl, N-1-carboxy-2-hydroxymethylcarbamoyl, N-[3-(2-oxopyrrolidin-1-yl)propyl]carbamoyl, N-(2-hydroxy-2-methylpropyl)carbamoyl, N-methoxy-N-methylcarbamoyl, N-2-(methylsulfonyl)ethylcarbamoyl, N-methoxypropylcarbamoyl, and methoxymethyl)ethyl]amino}carbamoyl;

n is 1; and

m is 1 or 2; wherein the values of R⁵ may be the same or different; or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, there is provided a compound of the invention which is a compound of formula (IA)

wherein:

R¹ is selected from hydrogen, halo, cyano, or C₁₋₄alkyl;

R² is selected from hydrogen, halo, cyano, or C₁₋₄alkyl;

R³ is selected from hydrogen, halo, cyano, C₁₋₄alkyl, or —C═N—OH;

X is a direct bond, —CH₂—, —C(O)— or S(O)_(q)— (wherein q is 1 or 2);

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R⁹;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, C₁₋₄alkoxyiminomethyl, N-hydroxyformamido, C₁₋₄hydrazino, hydrazinocarbonyl, N-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, N—(C₁₋₄alkoxy)carbamoyl, N′—C₁₋₄alkyl)ureido, N′,N′—(C₁₋₄alkyl)₂ureido, N—(C₁₋₄alkyl)-N—(C₁₋₄alkoxy)carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylamino, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkylsulphonylaminocarbonyl, N′—(C₁₋₄alkyl)hydrazinocarbonyl, N′,N′—(C₁₋₄alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹²; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹³;

R⁶ is hydrogen or C₁₋₄alkyl;

n is 1-4; wherein the values of R⁴ may be the same or different;

m is 0-4; wherein the values of R⁵ may be the same or different;

R¹² is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkylsulphonylamino, C₁₋₄alkoxycarbonylamino, carbocyclyl-R¹⁴— or heterocyclyl-R¹⁵—; wherein R¹² independently of each other may be optionally substituted on carbon by one or more R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R¹⁷;

R⁹, R¹³ and R¹⁷ are independently selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰, R¹¹, R¹⁴ and R¹⁵ are independently selected from a direct bond, —O—, —N(R¹⁸)—, —C(O)—, —N(R¹⁹)C(O)—, —C(O)N(R²⁰)—, —S(O)_(p)—, —SO₂N(R²¹)— or —N(R²²)SO₂—; wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently selected from hydrogen or C₁₋₄alkyl and p is 0-2;

R¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl;

or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, there is provided a compound of formula (IA) which is a compound of formula (IB):

wherein:

R⁴ is a substituent on carbon and is selected from methoxy, hydroxy, methoxycarbonyl, fluoro, allyloxy, propoxy, N,N-dimethylcarbamoyl, morpholinocarbonyl, N-ethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, dimethylaminomethyl, N-methyl-N-methoxycarbamoyl, methoxymethyl, methylaminomethyl, carboxy, N-methyl-N-methoxyxcarbamoyl, N-hydroxyethylcarbamoyl, hydroxymethyl, (methylthio)methyl, (methylsulfinyl)methyl, (methylsulfonyl)methyl, benzyloxy, propynyloxy, methoxyethoxy, methoxypropoxy, chloro, methyl, cyclopropylmethoxy, thiazolylmethoxy, ethoxy, oxyacetic acid, ethylaminocarbonyloxy, allylaminocarbonyloxy, pyridinylmethoxy, hydroxypropoxy, methoxy(methyl)amino, and azido;

R⁵ is a substituent on carbon and is selected from chloro, carboxy, carbamoyl, methyl, methoxymethyl, methoxy, N-(1-methyl-1-phenylethyl)carbamoyl, N-(methoxy)carbamoyl, methoxycarbonyl or ethoxycarbonyl, N-methoxycarbamoyl, formyl, (methoxyimino)methyl, isopropoxycarbonyl, ethoxy, morpholinocarbonyl, hydroxy-1-methylethyl, amino, methoxycarbonylamino, methylsulfonylamino, N-(1-methyl-1-phenylethyl)carbamoyl, N-2-morpholin-4-ylethylcarbamoyl, piperidinocarbonyl, N-methylcarbamoyl, N-2-hydroxyethylcarbamoyl, N-2-methoxyethylcarbamoyl, N-2-hydroxypropylcarbamoyl, N-2-hydroxy-1-methylethylcarbamoyl, N-isoxazolylcarbamoyl, N2,2-difluoroethylcarbamoyl, N-tetrahydrofuran-3-ylcarbamoyl, N-cyclopropylcarbamoyl, N-1-cyanocyclopropylcarbamoyl, N-2-fluorocyclopropylcarbamoyl, N-2-hydroxy-1,1-dimethylethylcarbamoyl, N-1-cyano-1-methylethylcarbamoyl, N-1-(hydroxymethyl-2-methoxy-2-oxoethylcarbamoyl, N-1,3-dioxolan-2-ylmethylcarbamoyl, N-3-(2-oxopyrrolidin-1-ylpropylcarbamoyl, N-pyridin-2-ylmethylcarbamoyl, N-2-(methylthio)ethylcarbamoyl, N-1,3-oxazol-2-ylmethylcarbamoyl, N-2-fluoroethylcarbamoyl, N-(2-hydroxy-2-methylpropyl)carbamoyl, morpholin-4-ylmethyl, tert-butylaminomethyl, piperidine-1-ylmethyl, (3-hydroxypyrrolidin-1-yl)methyl, (hydroxyimino)methyl, 1,1-difluoromethyl, azidomethyl, cyano(morpholin-4-yl)methyl, N-2-(methylsulfonyl)ethylcarbamoyl, cyano, 1-hydroxy-1-methylethyl, cyclopropylmethyl, N-methylcarbamoyl, N-1-carboxycycloproylcarbamoyl, N-isoxazol-3-ylcarbamoyl, N-prop-2-yn-1 ylcarbamoyl, N-1-carboxy-2-hydroxymethylcarbamoyl, N-[3-(2-oxopyrrolidin-1-yl)propyl]carbamoyl, N-(2-hydroxy-2-methylpropyl)carbamoyl, N-methoxy-N-methylcarbamoyl, N-2-(methylsulfonyl)ethylcarbamoyl, N-methoxypropylcarbamoyl, and methoxymethyl)ethyl]amino}carbamoyl;

n is 1; wherein the values of R⁴ may be the same or different; and

m is 1 or 2; wherein the values of R⁵ may be the same or different.

In a further aspect of the invention, there is provided a compound of formula (IB) which is a compound of formula (IC).

In a further aspect of the invention, there is provided a compound of formula (IC):

wherein:

Ring A is heterocyclyl; wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl.

In a further aspect of the invention, there is provided a compound of formula (IC) which is a compound of formula (IE):

wherein:

Y is N—H, N—C₁₋₄alkyl, S, or O;

R^(5a) is H or as defined for R⁵;

R^(5b) is H or as defined for R⁵; or

R^(5a) and R^(5b) taken together with the carbons to which they are attached form a 6-membered carbocyclyl ring substituted by one or two groups selected from R⁵ which may be the same or different.

In a further aspect of the invention, there is provided a compound of formula (IE) which is a compound of formula (IF):

Particular compounds of the invention are the compounds of the Examples, each of which provides a further independent aspect of the invention. In further aspects, the present invention also comprises any two or more compounds of the Examples.

In one embodiment of the invention are provided compounds of formula (I), in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I).

In a further aspect the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt thereof.

Thus, the present invention also provides that the compounds of the formula (I) and pharmaceutically-acceptable salts thereof, can be prepared by a process as follows (wherein the variables are as defined above unless otherwise stated)

Process a) for compounds of formula (I) wherein W is —C(R⁷)(R⁸)—; converting a compound of formula (II):

wherein R^(a) is cyano and R^(b) is dimethyamino or diethylamino; or R^(a) and R^(b) are independently selected from C₁₋₄alkylthio; or R^(a) and R^(b) together form 1,3-dithianyl or 1,3-dithiolanyl; into a compound of formula (I); Process b) for compounds of formula (I) wherein W is —O—; reacting a compound of formula (III):

with a compound of formula (IV):

Process c) for compounds of formula (I) wherein W is —N(R⁶)—; reacting a compound of formula (V):

with a compound of formula (IV) or an activated acid derivative thereof; Process d) for compounds of formula (I) wherein W is —C(R⁷)(R⁸)—; reacting a compound of formula (VI):

wherein L is a displaceable group; with a compound of formula (VII):

Process e) for compounds of formula (I) wherein W is —C(R⁷)(R⁸)—; reacting a compound of formula (VIII):

wherein M is an organometallic group; with a compound of formula (IX):

wherein L is a displaceable group; Process f) reacting a compound of formula (X):

with a compound of formula (XI):

wherein D is a displaceable group; Process g) for compounds of formula (I) wherein X is —C(O)—; reacting a compound of formula (X) with a compound of formula (XII):

and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of     the formula (I); -   ii) removing any protecting groups; -   iii) forming a pharmaceutically acceptable salt.

L is a displaceable group. Suitable values for L include halo, for example chloro and bromo, pentafluorophenoxy and 2,5-oxopyrrolidin-1-yloxy.

D is a displaceable group. Suitable values for D include halo, for example chloro, bromo and iodo, tosylate and mesylate.

M is an organometallic group, suitable values for M include organocuprates, for example CuLi, organozincs, Zn, or a Grignard reagent for example MgG where G is halo for example chloro.

Specific reaction conditions for the above reaction are as follows.

Process a) Compounds of formula (II) may be converted into compounds of formula (I):

-   (i) where R^(a) is cyano and R^(b) is dimethyamino or diethylamino;     in the presence of a base for example sodium hydroxide, in a     suitable solvent for example aqueous methanol at room temperature. -   (ii) wherein or R^(a) and R^(b) are independently selected from     C₁₋₄alkylthio; or R^(a) and R^(b) together form 1,3-dithianyl or     1,3-dithiolanyl; in the presence of a reagent such as a mercury,     copper or silver salt for example Hg(ClO₄)₂, CuCl₂ or AgNO₃/Ag₂O in     the presence of a suitable solvent for example methanol, acetone or     ethanol from a temperature ranging from room temperature to reflux.

Compounds of formula (II) may be prepared according to Scheme 1:

wherein Pg is a hydroxy protecting group as defined hereinbelow; and D is a displaceable group as defined hereinabove.

Deprotection of hydroxy protecting groups are well known in the art. Examples of such deprotections are given hereinbelow.

FGI stands for Functional Group Interconversion. In the above scheme such conversions between a hydroxy group and a D group are well known in the art and are well within the capabilities of a person skilled in the art.

Compounds of formula (IIa) and (IId) are known in the literature, or they are prepared by standard processes known in the art.

Process b) Compounds of formula (III) and (IV) may be reacted together may be reacted together in the presence of a coupling reagent, for example dicyclohexylcarbodiimide or EDC, in a suitable solvent, for example dichloromethane, THF or diethylether.

Compounds of formula (III) may be prepared according to Scheme 2:

wherein Pg is a hydroxy protecting group as defined hereinbelow.

Deprotection of hydroxy protecting groups are well known in the art. Examples of such deprotections are given hereinbelow.

Compounds of formula (IIIa) and (IV) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process c) Compounds of formula (V) and (IV) may be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature in the range of −40 to 40° C.

Compounds of formula (V) may be prepared according to Scheme 3:

wherein Pg is a amino protecting group as defined hereinbelow. The skilled reader will appreciate that where R⁶ is hydrogen, this hydrogen also needs protecting by way of a suitable protecting group.

Deprotection of amino protecting groups are well known in the art. Examples of such deprotections are given hereinbelow.

Compounds of formula (Va) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process d) Compounds of formula (VI) and (VII) may be reacted in a suitable solvent such a DCM or 1,2-dichloroethane, optionally in the presence of a Lewis acid, for example AlCl₃, from 0° C. to room temperature.

Compounds of formula (VI) may be prepared according to Scheme 4:

wherein R^(a)OC(O) is an ester group.

Suitable values for R^(a) include C₁₋₆alkyl. Deprotection of the R^(a) carboxy protecting group may be achieved under standard conditions, for example acid or base hydrolysis, such as those conditions give hereinbelow.

FGI stands for Functional Group Interconversion. In the above scheme such conversions between an acid group and a —C(O)L group are well known in the art and are well within the capabilities of a person skilled in the art.

Compounds of formula (VIa) and (VII) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process e) Compounds of formula (VIII) and (IX) may be reacted in a suitable aprotic solvent such as THF or ether, at temperatures in the range of −78° C. to 0° C.

Compounds of formula (VIII) may be prepared from compounds of formula (IIc) under standard conditions known in the art. For example where M is an organocuprous reagent such compounds could be prepared according to Scheme 5:

Compounds of formula (IX) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process f) Compounds of formula (X) and (XI) may be reacted in a suitable solvent such as DMF, N-methylpyrrolidinone or dimethylacetamide in the presence of a base such as triethylamine or diisopropylethylamine under thermal conditions or a microwave reactor.

Compounds of formula (X) may be prepared according to Scheme 6:

wherein M is an organometallic group as defined hereinabove.

Compounds of formula (Xa), (Xb) and (XI) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process g) Compounds of formula (X) and (XII) may be coupled together under the conditions outlined in Process c).

Compounds of formula (XII) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

The formation of a pharmaceutically-acceptable salt is within the skill of an ordinary organic chemist using standard techniques.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. The reagents used to introduce such ring substituents are either commercially available or are made by processes known in the art.

Introduction of substituents into a ring may convert one compound of the formula (I) into another compound of the formula (I). Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, formation of heteroaryl rings. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of alkoxides, diazotization reactions followed by introduction of thiol group, alcohol group, halogen group. Examples of modifications include; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 4^(th) Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).

Examples of a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.

A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.

When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.

Enzyme Potency Testing Methods

Compounds were tested for inhibition of GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97). Assays were performed in multiwell plates in 100 μl reactions containing: 50 mM TRIS buffer pH 7.5, 75 mM ammonium acetate, 5.5 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 16 μg/ml sheared salmon sperm DNA, 4 nM E. coli GyrA, 4 nM E. coli GyrB, 250 μM ATP, and compound in dimethylsulfoxide. Reactions were quenched with 150 μl of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates were read in an absorbance plate reader at 625 nm and percent inhibition values were calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and novobiocin-containing (2 μM) reactions as 100% inhibition controls. Compounds were tested for inhibition of topoisomeraseIV ATPase activity as described above for GyrB except the 100 μl reactions contained the following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1,4-Dithio-DL-threitol, 0.005% Brij-35, 5 μg/ml sheared salmon sperm DNA, 10 nM E. coli GyrA, 10 nM E. coli GyrB, 160 μM ATP, and compound in dimethylsulfoxide. Compound potency was based on IC₅₀ measurements determined from reactions performed in the presence of 10 different compound concentrations.

Compounds of the Examples generally have IC₅₀ values of <20 μg/ml.

Bacterial Susceptibility Testing Methods

Compounds were tested for antimicrobial activity by susceptibility testing in liquid media. Compounds were dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay were grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension was a 0.5 McFarland and a further 1 in 10 dilution was made into the same liquid medium to prepare the final organism suspension in 100 μL. Plates were incubated under appropriate conditions at 37 degrees C. for 24 hrs prior to reading. The Minimum Inhibitory Concentration was determined as the lowest drug concentration able to reduce growth by 80% or more.

Example 48 had an MIC of 0.13 μg/ml against Streptococcus pneumoniae. Other examples are provided in the following table.

Example MIC MIC MIC MIC No. HIN446 MCA445 SPN548 SAU516 MIC EFM073 333 4 0.13 0.063 2 0.5 60 4 0.25 2 2 8 315 2 0.13 0.5 4 4 345 0.25 0.031 0.03 0.5 0.13 294 0.031 0.001 0.0039 0.031 0.016

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

We have found that compounds of the present invention inhibit bacterial DNA gyrase and topoisomeraseIV and are therefore of interest for their antibacterial effects.

According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.

According to a further feature of the invention there is provided a method for inhibition of bacterial DNA gyrase and/or topoisomeraseIV in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore.

According to a further feature of the invention there is provided a method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore.

A further feature of the present invention is a compound of formula (I) and pharmaceutically acceptable salts thereof for use as a medicament. Suitably the medicament is an antibacterial agent.

According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomeraseIV in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in inhibition of bacterial DNA gyrase and/or topoisomeraseIV in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.

In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, (hereinafter in this section relating to pharmaceutical composition “a compound of this invention”) for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition that comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.

According to a further aspect of the invention there is provided a pharmaceutical composition that comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in producing an anti-bacterial effect in an warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition that comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in inhibition of bacterial DNA gyrase and/or topoisomeraseIV in an warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition that comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection in an warm-blooded animal, such as a human being.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful antibacterial agents (for example, macrolides, quinolones, β-lactams or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.

In addition to its use in therapeutic medicine, compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in-vitro and in-vivo test systems for the evaluation of the effects of inhibitors of DNA gyrase in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above other, pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and particular embodiments of the compounds of the invention described herein also apply.

EXAMPLES

The invention is now illustrated but not limited by the following Examples in which unless otherwise stated:—

-   (i) evaporations were carried out by rotary evaporation in-vacuo and     work-up procedures were carried out after removal of residual solids     by filtration; -   (ii) operations were carried out at ambient temperature, that is     typically in the range 18-26° C. and without exclusion of air unless     otherwise stated, or unless the skilled person would otherwise work     under an inert atmosphere; -   (iii) column chromatography (by the flash procedure) was used to     purify compounds and was performed on Merck Kieselgel silica     (Art. 9385) unless otherwise stated; -   (iv) yields are given for illustration only and are not necessarily     the maximum attainable; -   (v) the structure of the end-products of the invention were     generally confirmed by NMR and mass spectral techniques [proton     magnetic resonance spectra is quoted and was generally determined in     DMSO-d₆ unless otherwise stated using a Bruker DRX-300 spectrometer     operating at a field strength of 300 MHz. Chemical shifts are     reported in parts per million downfield from tetramethysilane as an     internal standard (δ scale) and peak multiplicities are shown thus:     s, singlet; d, doublet; AB or dd, doublet of doublets; dt, doublet     of triplets; dm, doublet of multiplets; t, triplet, m, multiplet;     br, broad; fast-atom bombardment (FAB) mass spectral data were     generally obtained using a Platform spectrometer (supplied by     Micromass) run in electrospray and, where appropriate, either     positive ion data or negative ion data were collected] or using     Agilent 1100 series LC/MSD equipped with Sedex 75ELSD, run in APCI     mode and, where appropriate, either positive ion data or negative     ion data were collected; optical rotations were determined at 589 nm     at 20° C. using a Perkin Elmer Polarimeter 341; reverse phase HPLC     was carried out using YMC Pack ODS-AQ (100×20 mmID, S-5μ particle     size, 12 nm pore size); -   (vi) each intermediate was purified to the standard required for the     subsequent stage and was characterised in sufficient detail to     confirm that the assigned structure was correct; purity was assessed     by HPLC, TLC, or NMR and identity was determined by infra-red     spectroscopy (IR), mass spectroscopy or NMR spectroscopy as     appropriate; -   (vii) in which the following abbreviations may be used:—

DMF is N,N-dimethylformamide; DMA is N,N-dimethylacetamide; TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; DMSO is dimethylsulfoxide; CDCl₃ is deuterated chloroform; MS is mass spectroscopy; APCI is atmospheric pressure chemical ionisation; EtOAc is ethyl acetate; MeOH is methanol; DIEA is diisopropylethylamine; TFA is trifluoroacetic acid; HATU is N—[(dimethylamino)-1H,2,3-triazolo[4,5-b-]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HOAT is 1-hydroxy-7-azabenzotriazole; NMP is N-methylpyrrolidinone; THF is tetrahydrofuran; EtOH is ethanol; LCMS is liquid chromatography/mass spectrometry; DCM is dichloromethane;

-   (viii) temperatures are quoted as ° C.; -   (ix) Smith Microwave Synthesizer refers to an equipment that uses     microwave energy to heat organic reactions in a short period of     time; it was used according to the manufacturers instruction and was     obtained from Personal Chemistry Uppsala AB; -   (x) Kugelrohr distillation refers to a piece of equipment that     distils liquids and heats sensitive compounds using air-bath oven     temperature; it was used according to the manufacturers instruction     and was obtained from Buchi, Switzerland or Aldrich, Milwaukee, USA; -   (xi) Where cis(±) or trans(±) is used it is to be understood that     this refers to a racemic mixture of the cis or the trans isomers,     (−) or (+) refers to the single enantiomer as does R,R or S,S where     quoted. Rotations were measured for the first chiral compound in the     synthetic scheme (see for example Intermediates 57 and 58) by     measuring the rotation of the effluent from the chiral column, using     a Perkin Elmer Polarimeter 341, at the point at which the enantiomer     eluted, the nomenclature cis(−) or cis (+) was then continued for     all the compounds in the synthesis (for example, Example 42 is the     final compound in the synthesis which started from Intermediate 57);     and -   (xii) GCMS is Gas phase chromatography (model 6890N) with Mass     Spectrometer (model 5973) manufactured by Agilent and was used     according to manufacturers instructions.

Example 1 Cis(±)methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate

Method 1

Cis(±)3,4-dichloro-N-(3-methoxypiperidin-4-yl)-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 50; 380 mg), methyl 2-bromo-1,3-thiazole-5-carboxylate (276 mg), were dissolved in anhydrous DMA (5 ml). DIEA (216 μl) was added and the mixture was heated at 120° C. for 7 hours (h). The mixture was diluted with EtOAc, washed well with citrate buffer, water, brine, and dried over Na₂SO₄. The organic phase was concentrated in vacuo to give the title compound as a brown solid (337 mg).

Method 2

Alternatively the title compounds were prepared using a Smith Microwave Synthesizer by subjecting the reaction mixture to single-mode microwave at 150° C. for 30 minutes (min.) or until the reaction is complete as judged by LCMS, using polar aprotic solvent such as DMA, NMP or 1-butyl-3-methyl imidazolium-tetrafluoroborate as reaction solvents. MS (ES) MH⁺: 447 for C₁₇H₂₀Cl₂N₄O₄S; NMR: 1.65 (m, 2H), 2.09 (s, 3H), 3.07 (m, 3H), 3.48 (m, 1H), 3.63 (s, 3H), 3.86 (m, 1H), 4.15 (m, 2H), 6.91 (d, 1H), 7.45 (s, 1H), 11.19 (s, 1H).

Examples 2-33

The following Examples were prepared by the procedure described in Example 1 from the starting materials (SM) indicated.

Ex Compound Data SM 2 methyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 447 for Intermediate 51 and dichloro-5-methyl-1H- C₁₇H₂₀Cl₂N₄O₄S; NMR: 1.87 methyl 2-bromo-1,3- pyrrol-2- (m, 2H), 2.05 (m, 2H), 2.27 (s, thiazole-5- yl)carbonyl]amino}-3- 3H), 3.01 (m, 2H), 3.25 (s, carboxylate methoxypiperidin-1-yl)-1,3- 3H), 3.65 (m, 1H), 3.83 (s, thiazole-5-carboxylate 3H), 4.12 (m, 1H), 4.46 (m, 2H), 7.40 (d, 1H), 8.00 (s, 1H), 12.38 (s, 1H) 3 methyl 2-((3R,4S)-4-{[(3,4- MS (ES) MH⁺: 447 for Intermediate 52 and dichloro-5-methyl-1H- C₁₇H₂₀Cl₂N₄O₄S; NMR: 1.89 methyl 2-bromo-1,3- pyrrol-2- (m, 2H), 2.11 (m, 2H), 2.23 (s, thiazole-5- yl)carbonyl]amino}-3- 3H), 3.33 (m, 2H), 3.46 (s, carboxylate methoxypiperidin-1-yl)-1,3- 3H), 3.59 (m, 1H), 3.85 (s, thiazole-5-carboxylate 3H), 4.09 (m, 1H), 4.46 (m, 2H), 7.31 (d, 1H), 7.92 (s, 1H), 12.30 (s, 1H) 4 Cis(±)methyl 2-(4-{[(3,4- MS (ES) MH⁺: 414 for Intermediate 56 and difluoro-5-methyl-1H- C₁₇H₂₀F₂N₄O₄S; NMR: 1.72 methyl 2-bromo-1,3- pyrrol-2- (m, 2H), 1.79 (s, 3H), 2.3 (m, thiazole-5- yl)carbonyl]amino}-3- 2H), 3.45 (s, 3H), 3.61 (s, 1H), carboxylate methoxypiperidin-1-yl)-1,3- 3.8 (s, 3H), 4.08 (m, 1H), 4.41 thiazole-5-carboxylate (m, 2H), 6.88 (d, 1H), 8.00 (s, 1H), 11.5 (brs, 1H) 5 Cis(±)methyl 2-(4-{[(3,4- dichloro-5-methyl-1H- pyrrol-2- yl)carbonyl]amino}-3- propoxypiperidin-1-yl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 475 for C₁₉H₂₄Cl₂N₄O₄S; NMR: 0.89 (m, 3H), 1.54 (m, 2H), 1.87 (m, 2H), 2.26 (s, 3H), 3.37 (m, 2H), 3.71 (m, 2H), 3.81 (s, 3H), 4.15 (m, 1H), 4.42 (m, 2H), 7.18 (d, 1H), 7.98 (s, 1H), 12.29 (s, 1H) Intermediate 53 and methyl 2-bromo-1,3- thiazole-5- carboxylate 6 Cis(±)methyl 2-(3- MS (ES) MH⁺: 473 for Intermediate 54 and (allyloxy)-4-{[(3,4- C₁₉H₂₂Cl₂N₄O₄S; NMR: 1.94 methyl 2-bromo-1,3- dichloro-5-methyl-1H- (m, 2H), 2.23 (s, 3H), 3.56 (m, thiazole-5- pyrrol-2- 2H), 3.58 (m, 2H), 3.84 (s, carboxylate yl)carbonyl]amino}piperidin- 3H), 4.07 (m, 2H), 4.21 (m, 1-yl)-1,3-thiazole-5- 1H), 4.46 (m, 2H), 5.37 (m, carboxylate 2H), 5.95 (m, 1H), 7.29 (d, 1H), 7.96 (s, 1H), 12.32 (s, 1H) 7 Cis(±)ethyl 4-(3-(allyloxy)- MS (ES) MH⁺: 531 for Intermediate 54 and 4-{[(3,4-dichloro-5-methyl- C₂₆H₂₈Cl₂N₄O₄ Intermediate 10 1H-pyrrol-2- yl)carbonyl]amino}piperidin- 1-yl)quinoline-2- carboxylate 8 Cis(±)ethyl 4-(4-{[(3,4- MS (ES) MH⁺: 533 for Intermediate 53 and dichloro-5-methyl-1H- C₂₆H₃₀Cl₂N₄O₄ Intermediate 10 pyrrol-2- yl)carbonyl]amino}-3- propoxypiperidin-1- yl)quinoline-2-carboxylate 9 Cis(±)methyl-2-(4-{[(3,4- MS (ES) MH⁺: 435, 437 for Intermediate 32 and dichloro-5-methyl-1H- C₁₆H₁₇Cl₂FN₄O₃S; NMR: methyl 2-bromo-1,3- pyrrol-2- 1.77-1.79 (m, 2H), 2.12 (s, thiazole-5- yl)carbonyl]amino}-3- 3H), 3.25-3.27 (m, 2H), 3.49- carboxylate fluoropiperidin-1-yl)-1,3- 3.62 (dd, 1H), 3.68 (s, 3H), thiazole-5-carboxylate 3.95 (m, 1H), 4.00-4.24 (m, 1H), 4.82-4.99 (m, 1H), 7.21 (d, 1H), 7.79 (s, 1H), 12.05 (brs, 1H) 10 Trans(±)methyl-2-(4-{[(3,4- MS (ES) MH⁺: 435, 437 for Intermediate 34 and dichloro-5-methyl-1H- C₁₆H₁₇Cl₂FN₄O₃S methyl 2-bromo-1,3- pyrrol-2- thiazole-5- yl)carbonyl]amino}-3- carboxylate fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylate

11 methyl 2-((3R,4S)-4-{[(3,4- MS (ES) MH⁺: 435, 437 for Intermediate 33 and dichloro-5-methyl-1H- C₁₆H₁₇Cl₂FN₄O₃S; NMR: methyl 2-bromo-1,3- pyrrol-2- 1.77-1.79 (m, 2H), 2.12 (s, thiazole-5- yl)carbonyl]amino}-3- 3H), 3.25-3.27 (m, 2H), 3.49- carboxylate fluoropiperidin-1-yl)-1,3- 3.62 (dd, 1H), 3.68 (s, 3H), thiazole-5-carboxylate 3.95 (m, 1H), 4.00-4.24 (m, 1H), 4.82-4.99 (m, 1H), 7.21 (d, 1H), 7.79 (s, 1H), 12.05 (brs, 1H) 12 Cis(±)ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 499, 501 for Intermediate 32 and dichloro-5-methyl-1H- C₁₆H₁₇Cl₂FN₄O₃S ethyl 2-bromo-1,3- pyrrol-2- benzothiazole-7- yl)carbonyl]amino}-3- carboxylate (U.S. Pat. fluoropiperidin-1-yl)-1,3- No. 5,770,758) benzothiazole-7- carboxylate 13 Cis(±)Ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 511, 513 for Intermediate 50 and dichloro-5-methyl-1H- C₂₂H₂₄Cl₂N₄O₄S; NMR: 1.45 ethyl 2-bromo-1,3- pyrrol-2- (t, 3H), 1.87 (m, 2H), 3.44 (s, benzothiazole-7- yl)carbonyl]amino}-3- 3H), 3.46 (m, 2H), 3.67 (m, carboxylate (U.S. Pat. methoxypiperidin-1-yl)-1,3- 1H), 4.23 (m, 1H), 4.28 (m, No. 5,770,758) benzothiazole-7- 1H), 4.36 (m, 1H), 4.47 (q, carboxylate 2H), 7.27 (d, 1H), 7.50 (t, 1H), 7.77 (t, 1H0, 12.26 (s, 1H) 14 Cis(±)Methyl 2-chloro-6- MS (ES) MH⁺: 477, 479 for Intermediate 50 and (4-{[(3,4-dichloro-5- C₁₈H₂₀Cl₃N₅O₄; NMR: 1.62 methyl 2,6- methyl-1H-pyrrol-2- (m, 1H), 1.77 (m, 1H), 2.18 (s, dichloropyrimidine- yl)carbonyl]amino}-3- 3H), 3.15 (m, 1H), 3.28 (s, 4-carboxylate methoxypiperidin-1- 3H), 3.56 (m, 1H), 3.87 (s, yl)pyrimidine-4-carboxylate 3H), 4.11 (m, 1H), 4.30 (m, 1H), 5.00 (m, 1H), 7.15 (m, 1H0, 7.36-7.48 (m, 1H), 12.16 (m, 1H) 15 Cis(±)Ethyl 2-(4-{[(4- chloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-4-carboxylate

MS (ES) MH⁺: 427, 429 for C₁₈H₂₃ClN₄O₃; NMR: 1.27 (t, 3H), 1.60 (m, 1H), 1.93 (m, 1H), 2.14 (s, 3H), 3.23 (m, 1H), 3.28 (s, 3H), 3.43 (m, 1H), 3.53 (m, 1H), 3.85 (m, 1H), 4.12 (m, 1H), 4.24 (m, 2H), 6.89 (s, 1H) Intermediate 55 and ethyl 2-bromo-1,3- thiazole-4- carboxylate 16 Cis(±)ethyl 2-(4-{[(3,4- MS (ES) (M + H): 461, 463 for Intermediate 50 and dichloro-5-methyl-1H- C₁₈H₂₂Cl₂N₄O₄S ethyl 2-bromo-1,3- pyrrol-2- thiazole-4- yl)carbonyl]amino}-3- carboxylate methoxypiperidin-1-yl)-1,3- thiazole-4-carboxylate 17 Cis(±)ethyl 4-(4-{[(3,4- MS (ES) MH⁺: 455 for Intermediate 50 and dichloro-5-methyl-1H- C₂₀H₂₄Cl₂N₄O₄ ethyl 4- pyrrol-2- chloropyridine-2- yl)carbonyl]amino}-3- carboxylate (WO methoxypiperidin-1- 2004007657) yl)pyridine-2-carboxylate 18 Cis(±)methyl 2-[4-{[(3,4- MS (ES) MH⁺: 461 for Intermediate 74 and dichloro-5-methyl-1H- C₁₈H₂₂Cl₂N₄O₄S methyl-2- pyrrol-2- bromothiazole-5- yl)carbonyl]amino}-3- carboxylate (methoxymethyl)piperidin- 1-yl]-1,3-thiazole-5- carboxylate 19 Cis(±)methyl-2-{4-{[(3,4- MS (ES) MH⁺: 460 for Intermediate 75 and dichloro-5-methyl-1H- C₁₈H₂₃Cl₂N₅O₃S methyl-2- pyrrol-2- bromothiazole-5- yl)carbonyl]amino}-3- carboxylate [(methylamino)methyl] piperidin-1-yl}-1,3-thiazole-5- carboxylate 20 Cis(±)methyl 2-{4-{[(3,4- MS (ES) MH⁺: 474 for Intermediate 76 and dichloro-5-methyl-1H- C₁₉H₂₅Cl₂N₅O₃S methyl-2- pyrrol-2- bromothiazole-5- yl)carbonyl]amino}-3- carboxylate [(dimethylamino)methyl] piperidin-1-yl}-1,3-thiazole- 5-carboxylate

21 Cis(±)methyl-2-(4-{[(4- MS (ES) MH⁺: 574 for Intermediate 16 and chloro-5-methyl-1H-pyrrol- C₂₇H₃₂ClN₅O₅S Intermediate 55 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- {[(1-methyl-1- phenylethyl)amino]carbonyl}- 1,3-thiazole-5- carboxylate 22 Cis(±)methyl-2-(4-{[(4- MS (ES) MH⁺: 413 for Intermediate 55 and chloro-5-methyl-1H-pyrrol- C₁₇H₂₁ClN₄O₄S; NMR: 1.63 methyl 2-bromo-1,3- 2-yl)carbonyl]amino}-3- (s, 1H), 1.90 (s, 1H), 2.14 (s, thiazole-5- methoxypiperidin-1-yl)-1,3- 3H), 3.28 (s, 3H), 3.39 (s, 1H), carboxylate thiazole-5-carboxylate 3.47 (s, 2H), 3.74 (s, 3H), 3.93 (s, 1H), 4.21 (s, 2H), 6.89 (d, J = 2.64 Hz, 1H), 7.71 (d, J = 7.91 Hz, 1H), 7.84 (s, 1H), 11.64 (s, 1H) 23 Cis(±)methyl-2-chloro-6- MS (ES) MH⁺: 442 for Intermediate 55 and (4-{[(4-chloro-5-methyl- C₁₈H₂₁Cl₂N₅O₄; NMR: 1.63 (s, methyl 2,6- 1H-pyrrol-2- 1H), 1.79 (s, 1H), 2.09-2.20 dichloropyrimidine- yl)carbonyl]amino}-3- (m, 3H), 3.08 (s, 1H), 3.17 (d, 4-carboxylate methoxypiperidin-1- J = 5.27 Hz, 1H), 3.25 (s, 3H), yl)pyrimidine-4-carboxylate 3.30 − 3.81 − 3.89 (m, 3H), 4.22 (s, 2H), 4.91 (s, 1H), 6.87 (d, J = 2.64 Hz, 1H), 7.37 (s, 1H), 7.67 (d, J = 7.72 Hz, 1H), 11.62 (s, 1H) 24 Cis(±)methyl-2-(4-{[(4- MS (ES) MH⁺: 457 for Intermediate 55 and chloro-5-methyl-1H-pyrrol- C₁₉H₂₅ClN₄O₅S; NMR: 1.63 Intermediate 17 2-yl)carbonyl]amino}-3- (s, 1H), 1.84-1.99 (m, 1H), methoxypiperidin-1-yl)-4- 2.12-2.19 (m, 3H), 3.33 (s, (methoxymethyl)-1,3- 3H), 3.35-3.38 (m, 1H), 3.52- thiazole-5-carboxylate 3.57 (m, 1H), 3.72 (s, 3H), 3.97 (s, 1H), 4.15-4.29 (m, 3H), 4.52-4.61 (m, 2H), 6.89 (d, J = 2.64 Hz, 1H), 7.70 (d, J = 7.91 Hz, 1H), 11.63 (s, 1H) 25 Cis(±)methyl-2-(4-{[(3,4- dichloro-5-methyl-1H- pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- (methoxymethyl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 491 for C₁₉H₂₄Cl₂N₄O₅S; NMR: 1.66- 1.81 (m, 2H), 2.14-2.22 (m, 3H), 3.29 (s, 3H), 3.33 (s, 2H), 3.36 (s, 3H), 3.55 (s, 1H), 3.73 (s, 3H), 3.97 (s, 1H), 4.20- 4.35 (m, 2H), 4.57 (d, J = 1.32 Hz, 2H), 7.15 (d, J = 8.29 Hz, 1H), 12.15 (s, 1H) Intermediate 50 and Intermediate 17 26 Cis(±)ethyl 4-(4-{[(4- MS (ES) MH⁺: 471 for Intermediate 55 and chloro-5-methyl-1H-pyrrol- C₂₄H₂₇ClN₄O₄; NMR: 1.38 (t, Intermediate 10 2-yl)carbonyl]amino}-3- J = 7.06 Hz, 3H), 1.80 (s, 1H), methoxypiperidin-1- 2.15 (s, 3H), 3.27 (s, 3H), 3.36- yl)quinoline-2-carboxylate 3.42 (m, 3H), 3.64 (s, 3H), 3.84 (s, 1H), 4.41 (q, J = 7.10 Hz, 2H), 6.95 (d, J = 2.64 Hz, 1H), 7.57 (s, 1H), 7.69 (d, J = 7.16 Hz, 1H), 7.73-7.82 (m, 2H), 8.11 (dd, J = 17.14, 8.29 Hz, 2H), 11.65 (s, 1H 27 Cis(±)ethyl-2-(4-{[(3,4- MS (ES) MH⁺: 455 for Intermediate 50 and dichloro-5-methyl-1H- C₂₀H₂₄Cl₂N₄O₄; NMR: 1.32 (t, ethyl 2- pyrrol-2- J = 7.06 Hz, 3H), 1.72 (d, fluoroisonicotinate yl)carbonyl]amino}-3- J = 0.75 Hz, 2H), 2.18 (s, 3H), (Konno, Akinori J. methoxypiperidin-1- 3.13 (d, J = 13.38 Hz, 2H), 3.29- Fluorine Chemistry yl)isonicotinate 3.31 (m, 3H), 3.50 (s, 1H), (1998), 87(2), 137- 4.23 (s, 2H), 4.32 (q, J = 7.03 140) Hz, 2H), 4.67 (s, 1H), 6.97 (dd, J = 5.09, 0.94 Hz, 1H), 7.14 (d, J = 8.10 Hz, 1H), 7.23 (s, 1H), 8.24 (d, J = 5.09 Hz, 1H), 12.15 (s, 1H) 28 Cis(±)ethyl-4-(4-{[(4- MS (ES) MH⁺: 421 for Intermediate 55 and chloro-5-methyl-1H-pyrrol- C₂₀H₂₅ClN₄O₄; NMR: 1.31 (t, ethyl 4- 2-yl)carbonyl]amino}-3- J = 7.06 Hz, 3H), 1.61 (s, 1H), chloropyridine-2- methoxypiperidin-1- 1.85 (s, 1H), 2.12-2.18 (m, carboxylate (WO yl)pyridine-2-carboxylate 3H), 3.23 (s, 3H), 3.50 (s, 1H), 2004007657) 3.89 (s, 2H), 4.19 (s, 3H), 4.30 (q, J = 7.16 Hz, 2H), 6.89 (d, J = 2.83 Hz, 1H), 7.05 (dd, J = 6.03, 2.64 Hz, 1H), 7.44 (d, J = 2.64 Hz, 1H), 7.67 (d, J = 8.10 Hz, 1H), 8.20 (d, J = 5.84 Hz, 1H), 11.63 (s, 1H) 29 Cis(±)3,4-dicholoro-N-[3- MS (ES) MH⁺: 447 for Intermediate 50 and methoxy-1-(2- C₂₂H₂₄Cl₂N₄O₂ 4-chloro-2- methylquinolin-4- methylquinoline yl)piperidin-4-yl]-5-methyl- 1H-pyrrole-2-carboxamide 30 Cis(±)Methyl 4-{[(3,4- dichloro-5-methyl-1H- pyrrol-2- yl)carbonyl]amino}-1-[5- (methoxycarbonyl)-1,3- thiazol-2-yl]piperidine-3- carboxylate

MS (ES) MH⁺: 474 C₁₈H₂₂ClN₅O₅S; NMR: 1.98 (m, 2H), 2.23 (s, 3H), 3.08 (m, 1H), 3.24 (m, 1H), 3.55 (m, 1H), 3.66 (s, 3H), 3.79 (s, 3H), 3.97 (m, 1H), 4.23 (m, 1H), 4.63 (m, 1H), 7.64 (d, 1H), 7.95 (s, 1H), 12.01 (s, 1H) Intermediate 35 and methyl 2-bromo-1,3- thiazole-5- carboxylate 31 Cis(±)ethyl 2-(4-{[(4- MS(ES) MH⁺: 477, 479 for Intermediate 55 and chloro-5-methyl-1H-pyrrol- C₂₂H₂₅ClN₄O₄S; NMR: 1.33 (t, ethyl 2-bromo-1,3- 2-yl)carbonyl]amino}-3- 3H), 1.76 (m, 1H), 1.83 (m, benzothiazole-7- methoxypiperidin-1-yl)-1,3- 1H), 2.10 (s, 3H), 3.37 (m, carboxylate (U.S. Pat. benzothiazole-7- 2H), 3.45 (s, 3H), 3.54 (m, No. 5,770,758) carboxylate 1H), 4.21-4.29 (m, 3H), 4.36 (q, 2H), 6.86 (m, 1H), 7.38 (t, 1H), 7.62-7.69 (m, 3H), 11.60 (s, 1H) 32 Cis(±)ethyl 4-(4-{[(3,4- MS (ES) MH: 472 for for Intermediate 56 and difluoro-5-methyl-1H- C₂₄H₂₆F₂N₄O₄ Intermediate 10 pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1- yl)quinoline-2-carboxylate 33 methyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 435, 437 for Intermediate 36 and dichloro-5-methyl-1H- C₁₆H₁₇Cl₂FN₄O₃S; NMR: 1.77- methyl 2-bromo-1,3- pyrrol-2- 1.79 (m, 2H), 2.12 (s, 3H), thiazole-5- yl)carbonyl]amino}-3- 3.25-3.27 (m, 2H), 3.49-3.62 carboxylate fluoropiperidin-1-yl)-1,3- (dd, 1H), 3.68 (s, 3H), 3.95 (m, thiazole-5-carboxylate 1H), 4.00-4.24 (m, 1H), 4.82- 4.99 (m, 1H), 7.21 (d, 1H), 7.79 (s, 1H), 12.05 (br s, 1H)

Example 34 Cis(±)methyl 4-(aminocarbonyl)-2-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate

Cis(±)methyl-2-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-1,3-thiazole-5-carboxylate (Example 21; 0.058 g, 0.1 mmol) was dissolved in equal volumes of TFA and DCM. The reaction was heated in a sealed tube to an external temperature of 85° C. overnight. The reaction mixture was concentrated to remove the DCM and excess TFA. The residue was partitioned with EtOAc and NaHCO₃ and the organic extracts were dried with MgSO₄ and concentrated to a yellow solid (0.050 g, 100%). MS (ES) MH⁺: 456 for C₁₈H₂₂ClN₅O₅S.

Example 35 Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid

Cis(±)methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 1; 200 mg) was dissolved in THF (50 ml). 2N LiOH (100 ml) was added and the mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to ambient and acidified with 20% aqueous citric acid. The aqueous phase was extracted with EtOAc and the organic phase was washed with water, brine, dried over Na₂SO₄. The organic phase was concentrated in vacuo and triturated with diethyl ether to give the title compound as an off white solid. (164 mg). MS (ES) MH⁺: 433, 431 for C₁₆H₁₈Cl₂N₄O₄S; NMR: 1.87 (m, 2H), 2.28 (s, 3H), 3.32 (m, 6H), 3.63 (s, 1H), 3.87 (m, 1H), 4.45 (m, 2H), 7.04 (d, 1H), 7.90 (s, 1H), 11.97 (s, 1H), 12.30 (s, 1H).

Examples 36-71

The following Examples were synthesized by an analogous method to Example 35 from the starting materials (SM) given in the table below.

Ex Compound NMR m/z SM 36 Cis(±)2-(4-{[(3,4-dichloro-5- 0.87 (m, 3H), 1.57 (m, 2H), 461 Example 5  methyl-1H-pyrrol-2- 1.93 (m, 2H), 2.24 (s, 3H), yl)carbonyl]amino}-3- 2.6 (m, 2H), 3.45 (m, 2H), propoxypiperidin-1-yl)-1,3- 3.69 (m, 2H), 4.36 (m, 2H), thiazole-5-carboxylic acid 7.23 (d, 1H), 7.87 (s, 1H), 12.34 (s, 1H) 37 Cis(±)2-(3-(allyloxy)-4-{[(3,4- 1.79 (m, 2H), 2.20 (s, 3H), 459 Example 6  dichloro-5-methyl-1H-pyrrol-2- 3.38 (m, 2H), 3.71 (s, 1H), yl)carbonyl]amino}piperidin-1- 3.95 (m, 2H), 4.15 (m, 2H), yl)-1,3-thiazole-5-carboxylic 5.26 (m, 2H), 5.91 (m, 1H), acid 7.18 (d, 1H), 7.76 (s, 1H), 12.19 (s, 1H) 38 Cis(±)4-(3-(allyloxy)-4-{[(3,4- 2.06 (m, 2H), 2.20 (s, 3H), 503 Example 7  dichloro-5-methyl-1H-pyrrol-2- 3.1-4.0 (m, 4H), 4.51 (m, yl)carbonyl]amino}piperidin-1- 3H), 5.18 (m, 2H), 5.82 (m, yl)quinoline-2-carboxylic acid 1H), 7.29 (d, 1H), 7.57 (s, 1H), 7.71 (m, 1H), 7.95 (m, 1H), 8.36 (m, 2H), 12.23 (s, 1H) 39 Cis(±)4-(4-{[(3,4-dichloro-5- 0.62 (t, 3H), 1.35 (m, 2H), 505 Example 8  methyl-1H-pyrrol-2- 2.13 (s, 3H), 5.36 (m, 2H), yl)carbonyl]amino}-3- 3.5-4.0 (m, 4H), 4.05 (m, propoxypiperidin-1- 2H), 4.43 (m, 2H), 7.20 (d, yl)quinoline-2-carboxylic acid 1H), 7.55 (s, 1H), 7.71 (m, 1H), 8.00 (m, 1H), 8.22 (m, 2H), 12.24 (s, 1H) 40 Cis(±)2-(4-{[(3,4-dichloro-5- 1.75-1.79 (m, 2H), 2.13 (s,  421, Example 9  methyl-1H-pyrrol-2- 3H), 3.39-3.57 (m, 2H), 3.93- 423 yl)carbonyl]amino}-3- 3.96 (d, 1H), 4.25 (m, 2H), fluoropiperidin-1-yl)-1,3- 4.81-4.97 (m, 1H), 7.28 (d, thiazole-5-carboxylic acid 1H), 7.63 (s, 1H), 12.12 (s, 1H)

41 Trans(±)2-(4-{[(3,4-dichloro-5- 1.74-1.79 (m, 2H), 2.11 (s,  421, Example 10 methyl-1H-pyrrol-2- 3H), 3.49-3.58 (m, 2H), 3.86- 423 yl)carbonyl]amino}-3- 3.92 (d, 1H), 4.22 (m, 2H), fluoropiperidin-1-yl)-1,3- 4.84-4.97 (m, 1H), 7.26 (d, thiazole-5-carboxylic acid 1H), 7.61 (s, 1H), 12.11 (s, 1H) 42 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.62-1.90 (m, 2H), 2.12 (s,  421, Example 33 methyl-1H-pyrrol-2- 3H), 3.23 (m, 1H), 3.50 (dd, 423 yl)carbonyl]amino}-3- 1H), 3.83-4.03 (m, 1H), 4.12- fluoropiperidin-1-yl)-1,3- 4.43 (m, 2H), 4.90 (d, 1H), thiazole-5-carboxylic acid 7.21 (d, 1H), 7.69 (s, 1H), 12.04 (s, 1H), 12.61 (brs, 1H) 43 2-((3R,4S)-4-{[(3,4-dichloro-5- 1.63-1.92 (m, 2H), 2.13 (s,  421, Example 11 methyl-1H-pyrrol-2- 3H), 3.21 (m, 1H), 3.50 (dd, 423 yl)carbonyl]amino}-3- 1H), 3.87-4.02 (m, 1H), 4.14- fluoropiperidin-1-yl)-1,3- 4.42 (m, 2H), 4.90 (d, 1H), thiazole-5-carboxylic acid 7.21 (d, 1H), 7.69 (s, 1H), 12.04 (s, 1H), 12.61 (brs, 1H) 44 Cis(±)2-(4-{[(3,4-dichloro-5- 1.82 (m, 2H), 2.13 (s, 3H),  471, Example 12 methyl-1H-pyrrol-2- 3.48-3.67 (m, 2H), 4.12-4.41 473 yl)carbonyl]amino}-3- (m, 3H), 4.92 (d, 1H), 7.22 (d, fluoropiperidin-1-yl)-1,3- 1H), 7.34 (t, 1H), 7.62 (m, 1H), benzothiazole-7-carboxylic acid 12.06 (s, 1H), 13.45 (brs, 1H) 45 Cis(±)2-(4-{[(3,4-dichloro-5- 1.86 (m, 2H), 2.25 (s, 3H), 3.46  483, Example 13 methyl-1H-pyrrol-2- (s, 3H), 3.48 (m, 2H), 3.65 (m, 485 yl)carbonyl]amino}-3- 1H), 4.35 (m, 2H), 4.46 (m, methoxypiperidin-1-yl)-1,3- 1H), 7.25 (d, 1H), 7.48 (t, 1H), benzothiazole-7-carboxylic acid 7.73 (t, 1H), 12.26 (s, 1H)

46 Cis(±)2-(4-{[(4-chloro-5- 1.60 (m, 1H), 1.83 (m, 1H),  449, Example 31 methyl-1H-pyrrol-2- 2.07 (s, 3H), 3.25 (s, 3H), 451 yl)carbonyl]amino}-3- 3.35 (m, 2H), 3.52 (m, 1H), methoxypiperidin-1-yl)-1,3- 4.09-4.17 (m, 3H), 6.84 (d, benzothiazole-7-carboxylic acid 1H), 7.37 (t, 1H), 7.58-7.67 (m, 3H), 11.58 (s, 1H) 47 Cis(±)2-(4-{[(3,4-dichloro-5- 1.74 (m, 2H), 2.17 (s, 3H),  433, Example 16 methyl-1H-pyrrol-2- 3.26 (m, 2H), 3.35 (s, 3H), 435 yl)carbonyl]amino}-3- 3.52 (m, 1H), 3.84 (m, 1H), methoxypiperidin-1-yl)-1,3- 4.21 (m, 2H), 7.13 (d, 1H), thiazole-4-carboxylic acid 7.57 (s, 1H), 12.15 (s, 1H), 12.61 (brs, 1H) 48 Cis(±)2-Chloro-6-(4-{[(3,4- 1.59 (m, 1H), 1.77 (m, 1H),  463, Example 14 dichloro-5-methyl-1H-pyrrol-2- 2.18 (s, 3H), 3.16 (m, 1H), 465 yl)carbonyl]amino}-3- 3.17 (m, 1H), 3.56 (m, 1H), methoxypiperidin-1- 4.11 (m, 1H), 4.30 (m, 1H), yl)pyrimidine-4-carboxylic acid 4.55 (m, 1H), 4.98 (m, 1H), 7.15 (m, 1H), 7.38 (m, 1H), 12.10 (m, 1H) 49 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.85 (m, 2H), 2.24 (s, 3H), 433 Example 2  methyl-1H-pyrrol-2- 3.32 (s, 3H), 3.42 (m, 2H), yl)carbonyl]amino}-3- 3.69 (s, 1H), 4.07 (m, 1H), methoxypiperidin-1-yl)-1,3- 4.49 (m, 2H), 7.31 (d, 1H), thiazole-5-carboxylic acid 7.87 (s, 1H), 12.27 (s, 1H), 12.69 (s, 1H) 50 Cis(±)2-(4-{[(4-chloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-4-carboxylic acid

1.61 (m, 1H), 1.92 (m, 1H), 2.14 (s, 3H), 3.24 (m, 1H), 3.28 (s, 3H), 3.43 (m, 1H), 3.53 (m, 1H), 3.84 (m, 1H), 4.10 (m, 1H), 4.21 (m, 1H), 6.91 (s, 1H), 7.51 (s, 1H), 7.69 (m, 1H), 11.64 (s, 1H)  399, 401 Example 15 51 2-((3S,4S)-4-{[(3,4-Dichloro-5- 1.64 (m, 1H), 1.88 (m, 1H),  433, Example 86 methyl-1H-pyrrol-2- 2.11 (s, 3H), 3.13-3.20 (m, 435 yl)carbonyl]amino}-3- 3H), 3.29 (s, 3H), 3.68 (m, methoxypiperidin-1-yl)-1,3- 1H), 4.03 (m, 1H), 7.29 (d, thiazole-5-carboxylic acid 1H0, 7.71 (s, 1H), 11.95 (s, 1H), 12.63 (brs, 1H) 52 2-((3R,4R)-4-{[(3,4-Dichloro-5- 1.63 (m, 1H), 1.88 (m, 1H),  433, Example 85 methyl-1H-pyrrol-2- 2.11 (s, 3H), 3.16-3.27 (m, 435 yl)carbonyl]amino}-3- 3H), 3.29 (s, 3H), 3.69 (m, methoxypiperidin-1-yl)-1,3- 1H), 4.03-4.07 (m, 2H), 7.37 thiazole-5-carboxylic acid (d, 1H), 7.69 (s, 1H), 12.03 (s, 1H) 53 Cis(±)2-[4-{[(3,4-dichloro-5- 1.62 (m, 1H), 2.03 (m, 1H), 447 Example 18 methyl-1H-pyrrol-2- 2.16 (s, 3H), 2.98 (m, 1H), yl)carbonyl]amino}-3- 3.21 (s, 3H), 3.25 (m, 3H), (methoxymethyl)piperidin-1- 3.41 (dd, 1H), 3.89 (m, 2H), yl]-1,3-thiazole-5-carboxylic 4.06 (dd, 1H), 7.51 (d, 1H), acid 7.63 (s, 1H) 54 Cis(±)2-{4-{[(3,4-dichloro-5- 1.63 (m, 1H), 1.83 (m, 1H), 446 Example 19 methyl-1H-pyrrol-2- 1.97 (m, 1H), 2.18 (s, 3H), yl)carbonyl]amino}-3- 2.44 (s, 3H), 2.64 (m, 1H), [(methylamino)methyl]piperidin- 2.79 (m, 1H), 2.98 (m, 2H), 1-yl}-1,3-thiazole-5-carboxylic 3.87 (m, 1H), 4.07 (m, 2H), acid 7.33 (s, 1H), 8.14 (d, 1H) 55 Cis(±)2-{4-{[(3,4-dichloro-5- 1.66 (m, 1H), 1.88 (m, 1H0, 460 Example 20 methyl-1H-pyrrol-2- 2.05 (m, 1H), 2.16 (s, 3H), 2.26 yl)carbonyl]amino}-3- (s, 6H), 2.40 (m, 2H), 2.94 (t, [(dimethylamino)methyl]piperidin- 1H), 3.18 (t, 1H), 3.86 (m, 1H), 1-yl}-1,3-thiazole-5- 3.98 (dd, 2H), 7.63 (s, 1H), carboxylic acid 7.67 (d, 1H), 12.3 (brs, 1H)

56 Cis(±)2-(4-{[(4-chloro-5- 1.63 (d, J = 3.39 Hz, 1H), 1.84- 399 Example 22 methyl-1H-pyrrol-2- 1.99 (m, 1H), 2.14 (s, 3H), yl)carbonyl]amino}-3- 3.28 (s, 3H), 3.54 (s, 1H), methoxypiperidin-1-yl)-1,3- 3.91 (s, 1H), 4.15-4.29 (m, thiazole-5-carboxylic acid 1H), 6.90 (d, J = 2.83 Hz, 1H), 7.71 (d, J = 8.10 Hz, 1H), 7.74 (s, 1H), 11.64 (d, J = 1.70 Hz, 1H), 12.62 (s, 1H) 57 Cis(±)2-chloro-6-{4-{[(4- 1.64 (s, 1H), 1.78 (s, 1H), 2.13 428 Example 23 chloro-5-methyl-1H-pyrrol-2- (s, 3H), 3.13 (s, 1H), 3.25 (s, yl)carbonyl]amino}-3- 3H), 3.54 (s, 1H), 4.22 (s, 2H), methoxypiperidin-1- 4.60 (s, 1H), 4.93 (s, 1H), 6.87 yl)pyrimidine-4-carboxylic acid (d, J = 2.45 Hz, 1H), 7.34 (s, 1H), 7.65 (s, 1H), 11.62 (s, 1H), 13.69 (s, 1H) 58 Cis(±)2-(4-{[(4-chloro-5- 1.62 (s, 1H), 1.93 (s, 1H), 443 Example 24 methyl-1H-pyrrol-2- 2.14 (s, 3H), 3.28 (d, J = 2.26 yl)carbonyl]amino}-3- Hz, 3H), 3.36 (s, 3H), 3.54 (s, methoxypiperidin-1-yl)-4- 2H), 3.91 (s, 1H), 4.19 (s, (methoxymethyl)-1,3-thiazole- 2H), 4.56 (s, 2H), 6.89 (s, 1H), 5-carboxylic acid 7.69 (s, 1H), 11.63 (s, 1H) 59 Cis(±)2-(4-{[(3,4-dichloro-5- 1.75 (s, 2H), 2.18 (s, 3H), 477 Example 25 methyl-1H-pyrrol-2- 3.28 (s, 3H), 3.37 (s, 3H), yl)carbonyl]amino}-3- 3.54 (s, 3H), 3.91 (s, 1H), methoxypiperidin-1-yl)-4- 4.26 (s, 2H), 4.56 (s, 2H), (methoxymethyl)-1,3-thiazole- 7.14 (s, 1H), 12.15 (s, 1H) 5-carboxylic acid 60 Cis(±)4-(4-{[(4-chloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1- yl)quinoline-2-carboxylic acid

1.80 (s, 1H), 2.15 (s, 3H), 3.15 (s, 3H), 3.64 (s, 3H), 3.80 (s, 2H), 4.09 (s, 1H), 4.30 (s, 1H), 6.93 (d, J = 2.45 Hz, 1H), 7.57 (s, 1H), 7.68 (s, 1H), 7.85 (s, 2H), 8.19 (s, 2H), 11.65 (s, 1H) 443 Example 26 61 Cis(±)4-(4-{[(3,4-dichloro-5- 1.67 (s, 1H), 1.81 (s, 1H), 393 Example 17 methyl-1H-pyrrol-2- 2.18 (s, 3H), 3.28 (s, 3H), yl)carbonyl]amino}-3- 3.59 (s, 2H), 4.20 (s, 2H), methoxypiperidin-1- 4.32 (s, 1H), 4.55 (d, J = 12.43 yl)pyridine-2-carboxylic acid Hz, 1H), 7.14 (d, J = 8.29 Hz, 1H), 7.18 (dd, J = 7.06, 2.92 Hz, 1H), 7.44 (d, J = 2.64 Hz, 1H), 7.97 (d, J = 6.97 Hz, 1H), 12.18 (s, 1H) 62 Cis(±)2-(4-{[(3,4-dichloro-5- 1.72 (s, 2H), 2.18 (s, 3H), 427 Example 27 methyl-1H-pyrrol-2- 3.04-3.18 (m, 2H), 3.30 (s, yl)carbonyl]amino}-3- 3H), 3.49 (s, 1H), 4.25 (s, methoxypiperidin-1- 2H), 4.66 (s, 1H), 6.97 (d, yl)isonicotinic acid J = 4.71 Hz, 1H), 7.16 (s, 1H), 7.24 (s, 1H), 8.22 (d, J = 4.90 Hz, 1H), 12.16 (s, 1H), 13.39 (s, 1H) 63 Cis(±)2-[4-{[(3,4-Dichloro-5- MS (ES⁺): 516, 518 for Example 78 methyl-1H-pyrrol-2- C₂₀H₂₃Cl₂N₄O₅S; NMR: 1.82 yl)carbonyl]amino}-3- (m, 2H), 2.15 (s, 3H), 3.32 (morpholin-4- (m, 6H), 3.61 (m, 5H), 3.99 ylcarbonyl)piperidin-1-yl]-1,3- (t, 2H), 4.40 (m, 1H), 7.18 (d, thiazole-5-carboxylic acid 1H), 7.78 (s, 1H), 12.03 (s, 1H), 12.8 (brs, 1H) 64 Cis(±)2-{4-{[(3,4-Dichloro-5- 1.75 (m, 1H), 1.89 (m, 1H),  474, Example 79 methyl-1H-pyrrol-2- 2.14 (s, 3H), 2.87 (s, 3H), 476 yl)carbonyl]amino}-3- 3.09 (s, 3H), 3.36 (m [under [(dimethylamino)carbonyl] water peak], 3H), 4.00 (m, piperidin-1-yl}-1,3-thiazole-5- 2H), 4.36 (m, 1H), 7.19 (d, carboxylic acid 1H), 7.78 (s, 1H), 11.98 (s, 1H), 12.71 (brs, 1H) 65 Cis(±)2-{4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- [(ethylamino)carbonyl]piperidin- 1-yl}-1,3-thiazole-5-carboxylic acid

0.92 (t, 3H), 1.58 (m 1H), 1.99 (d, 1H), 2.15 (s, 3H), 2.62 (dd, 1H), 3.02 (m, 2H), 3.30 (q, 2H), 3.92 (d, 1H), 4.07 (d, 1H), 4.27 (m, 1H), 7.03 (d, 1H), 7.77 (s, 1H), 7.92 (t, 1H), 12.01 (s, 1H), 12.71 (brs, 1H)  474, 476 Example 80 66 Cis(±)2-(4-{[(3,4-dichloro-5- 1.50 (m, 1H), 1.96 (d, 1H),  490, Example 81 methyl-1H-pyrrol-2- 2.41 (s, 3H), 2.61 (m, 1H), 492 yl)carbonyl]amino}-3-{[(2- 3.07 (m, 2H), 3.26 (q, 2H), hydroxyethyl)amino]carbonyl} 3.32 (under water peak, 2H), piperidin-1-yl)-1,3-thiazole-5- 3.89 (d, 1H), 4.04 (d, 1H), carboxylic acid 4.22 (m, 1H), 4.72 (brs, 1H), 7.39 (brs, 1H), 7.62 (s, 1H), 8.07 (t, 1H), 12.32 (brs, 1H) 67 Cis(±)2-(4-{[(3,4-dichloro-5- 1.66 (m, 1H), 1.85 (m, 1H),  490, Example 82 methyl-1H-pyrrol-2- 2.14 (s, 3H), 3.08 (m, 1H), 492 yl)carbonyl]amino}-3- 3.09 (s, 3H), 3.15 (m, 1H), {[methoxy(methyl)amino] 3.33 (under water peak, 1H), carbonyl}piperidin-1-yl)-1,3- 3.74 (brs, 3H), 3.83 (m, 1H), thiazole-5-carboxylic acid 4.00 (m, 1H), 4.33 (m, 1H), 7.19 (s, 1H), 7.81 (brs, 1H), 12.98 (brs, 1H) 68 Cis(±)4-(aminocarbonyl)-2-(4- 1.63 (s, 1H), 1.90 (s, 1H), 442 Example 34 {[(4-chloro-5-methyl-1H- 2.14 (s, 3H), 3.17 (s, 1H), pyrrol-2-yl)carbonyl]amino}-3- 3.37 (s, 3H), 3.54 (s, 2H), methoxypiperidin-1-yl)-1,3- 4.14-4.28 (m, 2H), 6.90 (s, thiazole-5-carboxylic acid 1H), 7.72 (s, 1H), 8.93 (s, 2H), 11.63 (s, 1H) 69 2-((3R,4S)-4-{[(3,4-dichloro-5- 1.89 (m, 2H), 2.11 (s, 3H), 433 Example 3  methyl-1H-pyrrol-2- 2.23 (s, 3H), 3.33 (m, 2H), yl)carbonyl]amino}-3- 3.46 (s, 3H), 3.59 (s, 1H), methoxypiperidin-1-yl)-1,3- 4.09 (m, 1H), 4.46 (m, 2H), thiazole-5-carboxylic acid1,3- 7.31 (d, 1H), 7.92 (s, 1H), thiazole-5-carboxylic acid 12.28 (s, 1H), 12.67 (brs, 1H) 70 Cis(±)2-(4-{[(3,4-difluoro-5- 1.75 (m, 2H), 2.13 (s, 3H), 441 Example 4  methyl-1H-pyrrol-2- 3.33 (s, 3H), 3.36 (m, 2H), yl)carbonyl]amino}-3- 3.54 (s, 1H), 3.89 (m, 1H), methoxypiperidin-1-yl)-1,3- 3.94 (m, 2H), 6.73 (d, 1H), thiazole-5-carboxylic acid 7.90 (s, 1H), 11.40 (s, 1H)

71 Cis(±)4-(4-{[(3,4-difluoro-5- 1.69 (m, 2H), 2.01 (s, 3H), 444 Example 32 methyl-1H-pyrrol-2- 3.16 (m, 1H), 3.16 (s, 3H), yl)carbonyl]amino}-3- 3.8-4.02 (m, 2H), 4.18-4.38 methoxypiperidin-1- (m, 2H), 6.57-6.84 (d, 1H), yl)quinoline-2-carboxylic acid 7.44-7.56 (s, 1H), 7.56-7.72 (m, 1H), 7.78-7.94 (m, 1H), 8.04-8.27 (m, 2H), 11.23 (br, 1H)

Example 72 Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-N-methoxy-1,3-thiazole-5-carboxamide

Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 35; 100 mg) was dissolved in anhydrous DMA (2 ml). HATU (97 mg), HOAT (31 mg), DIEA (41 μl) were added and the mixture was stirred for 30 min. N-Methoxyamine hydrochloride (19.3 mg) was added followed by DIEA (41 μl), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed with H₂O, 20% citric acid solution, H₂O, sat. NaHCO₃, H₂O, brine and dried over Na₂SO₄. The organic phase was concentrated in vacuo to give the title compound as an off-white solid (82 mg). MS (ES)(MH⁺): 462, 460 for C₁₇H₂₁Cl₂N₅O₄S; NMR: 1.64 (m, 2H), 1.85 (m, 1H), 2.05 (s, 3H), 2.83 (m, 1H), 3.33 (m, 5H), 3.73 (s, 3H), 4.07 (m, 1H), 4.38 (m, 2H), 7.24 (d, 1H), 7.74 (s, 1H), 11.39 (s, 1H), 12.05 (s, 1H).

Example 73

The following Example was prepared by the procedure described in Example 72 from the starting material (SM) indicated.

Ex Compound Data SM 73 2-((3R,4R)-4-{[(3,4-Dichloro- MS (ES) (M + H): 462, Example 52 5-methyl-1H-pyrrol-2- 464 (M + H), for C₁₇H₂₁Cl₂N₅O₄S; yl)carbonyl]amino}-3- NMR: 1.61 (m, 1H), 1.87 (m, methoxypiperidin-1-yl)-N- 1H), 2.11 (s, 3H), 3.14 (m, methoxy-1,3-thiazole-5- 1H), 3.29 (s, 3H), 3.33 (m, carboxamide 1H), 3.59 (s, 3H), 3.64 (m, 1H,) 3.95-4.06 (m, 3H), 7.29 (d, 1H), 7.66 (s, 1H), 11.31 (brs, 1H), 11.95 (s, 1H)

Example 74 Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-hydroxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid

Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 35; 100 mg) was suspended in anhydrous DCM. BBr₃/DCM (15 ml) was added and the mixture was heated at 40° C. for 18 h. The reaction mixture was cooled to −50° C. and water was added. The mixture was extracted with EtOAc and the organic phase was washed with water, dried over Na₂SO₄. The organic phase was concentrated in vacuo to yield a pale brown solid which was dissolved in acetonitrile/water mixture and was lyophilized (46 mg). MS (ES) MH⁺: 419 for C₁₅H₁₆Cl₂N₄O₄S; NMR: 1.87 (m, 2H), 2.20 (s, 3H), 3-4 (brm, 6H), 6.9 (d, 1H), 7.51 (s, 1H), 12.19 (s, 1H).

Example 75

The following Example was prepared by the procedure described in Example 74 from the starting material (SM) indicated.

Ex Compound Data SM 75 Cis(±)4-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 463 for Example 76 methyl-1H-pyrrol-2- C₂₁H₂₀Cl₂N₄O₄; NMR: 1.24 (m, yl)carbonyl]amino}-3- 2H), 2.13 (m, 2H), 2.38 (s, 3H), 3.54 hydroxypiperidin-1- (m, 2H), 4.14 (m, 2H), 4.57 (m, 1H), yl)quinoline-2-carboxylic acid 7.07 (s, 1H), 7.87 (m, 1H), 8.23

(m, 2H), 8.52 (m, 2H), 12.06 (s, 1H)

Example 76 Cis(±)-4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)quinoline-2-carboxylic acid

Cis(±)3,4-dicholoro-N-[3-methoxy-1-(2-methylquinolin-4 -yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 29; 170 mg) was dissolved in pyridine (5 ml). Selenium dioxide (211 mg) was added and the mixture was heated at 130° C. for 3 h. The brown solution was cooled to room temperature, diluted with water and filtered through a bed of celite. The filtrate was extracted with EtOAc, washed with water and dried over Na₂SO₄, concentrated in vacuo. The brown solid that separated was triturated with Et₂O, filtered, washed well with n-hexanes and dried in vacuo to give the title compound as a brown solid (176 mg). MS (ES) MH⁺: 477 for C₂₂H₂₂Cl₂N₄O₄; NMR: 1.34 (m, 1H), 2.01 (m, 1H), 2.28 (s, 3H), 3.10 (s, 3H), 3.42 (m, 3H), 3.72 (m, 2H), 4.23 (m, 1H), 7.36 (d, 1H), 7.63 (s, 1H), 7.78 (m, 1H), 7.92 (m, 1H), 8.30 (m, 2H), 12.30 (brs, 1H).

Example 77 Cis(±)4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-[5-(methoxycarbonyl)-1,3-thiazol-2-yl]piperidine-3-carboxylic acid

Cis(±)4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-3-carboxylic acid hydrochloride (Intermediate 79; 1.84 g) was dissolved in anhydrous DMF (20 ml) under an argon atmosphere in a 100-ml round bottom flask. Methyl 2-bromothiazole-5-carboxylate (1.43 g) was added followed by N,N-diisopropylethylamine (3.6 ml) at room temperature. The reaction was heated to 55° C. for 14 h cooled to room temperature. The reaction mixture was diluted with EtOAc (250 ml) and washed with a saturated aqueous ammonium chloride solution (125 ml), followed by a saturated aqueous sodium chloride solution (100 ml). The EtOAc solution was dried over anhydrous MgSO₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0-10% CH₃OH in DCM. The recovered product was recrystallised from EtOAc to further enhance the diastereomeric excess, increasing it from a 90:10 cis:trans mixture to a 96:4 cis:trans mixture (by HPLC analysis). The recrystallised product was carried on to the next reaction (2 g). MS (ES−(M+H)⁺): 461, 463 for C₁₇H₁₈Cl₂N₄O₅S; NMR: 1.71 (m, 1H), 1.91 (m, 1H), 2.16 (s, 3H), 2.81 (dt, 1H), 3.42 (m, 2H), 3.74 (s, 3H), 3.86 (m, 1H), 4.34 (m, 2H), 7.43 (d, 1H), 7.88 (s, 1H), 8.50 (brs, 1H), 12.06 (s, 1H).

Example 78 Cis(±)methyl 2-[4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(morpholin-4-ylcarbonyl)piperidin-1-yl]-1,3-thiazole-5-carboxylate

The title compound was prepared in a manner analogous to (Intermediate 37) starting from cis(±)4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-[5-(methoxycarbonyl)-1,3-thiazol-2-yl]piperidine-3-carboxylic acid (Example 77) and morpholine. MS (ES⁺): 530, 532 for C₂₁H₂₅Cl₂N₅O₅S.

Examples 79-82

The following compounds were synthesized by an analogous method to Example 78 from Example 77 and the starting materials given in the table below.

Ex Compound m/z SM 79 Cis(±)methyl 2-{4-{[(3,4- M/z 488, 490 Dimethylamine dichloro-5-methyl-1H-pyrrol-2- (2 M in THF) yl)carbonyl]amino}-3- [(dimethylamino)carbonyl] piperidin-1-yl}-1,3-thiazole-5- carboxylate 80 Cis(±)methyl 2-{4-{[(3,4- M/z 488, 490 Ethylamine (2 dichloro-5-methyl-1H-pyrrol-2- M in THF) yl)carbonyl]amino}-3- [(ethylamino)carbonyl] piperidin-1-yl}-1,3-thiazole-5- carboxylate

81 Cis(±)methyl 2-(4-{[(3,4- M/z 504, 506 Ethanolamine dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3-{[(2- hydroxyethyl)amino]carbonyl} piperidin-1-yl)-1,3-thiazole-5- carboxylate 82 Cis(±)methyl 2-(4-{[(3,4- M/z 504, 506; NMR: 1.78 (m, N,O-Dimethyl- dichloro-5-methyl-1H-pyrrol-2- 1H), 1.93 (m, 1H), 2.14 (s, 3H), hydroxylamine yl)carbonyl]amino}-3- 3.06 (brs, 3H), 3.24 (m, 1H), 3.32 hydrochloride {[methoxy(methyl)amino] (s, 1H), 3.38 (m, 1H), 3.72 (brs, carbonyl}piperidin-1-yl)-1,3- 1H), 3.74 (s, 3H), 3.98 (m, 1H), thiazole-5-carboxylate 4.12 (m, 1H), 4.38 (m, 1H), 7.19 (d, 1H), 7.88 (s, 1H), 11.99 (s, 1H)

Example 83 Cis(±)6-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methoxypyrimidine-4-carboxylic acid

Cis(±)methyl 2-chloro-6-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylate (Example 23; 0.12 g, 0.27 mmol) was dissolved in 0.5 M sodium methoxide in MeOH (5.4 ml, 2.7 mmol) and heated in the microwave for 1.5 h at 85° C. The reaction mixture was acidified with 1N HCl and the product was extracted with EtOAc, dried with MgSO₄ and concentrated to a solid which was purified by reverse phase chromatography (gradient elution from 20-50% CH₃CN in water with 0.5% TFA). Freeze drying yielded product as a white solid. MS (ES) MH⁺: 424 for C₁₈H₂₂ClN₅O₅; NMR: 1.62 (s, 1H), 1.75 (s, 1H), 2.14 (s, 3H), 3.26 (s, 3H), 3.53 (m, 3H), 3.87 (s, 3H), 4.22 (s, 2H), 6.88 (d, J=2.64 Hz, 1H), 7.07 (s, 1H), 7.66 (d, J=7.91 Hz, 1H), 11.63 (s, 1H).

Example 84

The following compound was prepared by the procedure of Example 83 from the starting material (SM) indicated.

Ex Compound NMR M/z SM 84 Cis(±)6-(4-{[(3,4-dichloro-5- 1.61 (m, 1H), 1.74 (m, 1H), 458, Example methyl-1H-pyrrol-2- 2.18 (s, 3H), 3.21 (m, 1H), 3.33 (s, 3H), 460 14 yl)carbonyl]amino}-3- 3.51 (m, 1H), 3.53 (m, 1H), methoxypiperidin-1-yl)-2- 3.85 (s, 3H), 4.28 (m, 2H), 5.10 (m, methoxypyrimidine-4- 1H), 7.03 (m, 1H), 7.12 (m, 1H), carboxylic acid 12.15 (m, 1H)

Examples 85-86

The following compounds were prepared by the procedure of Intermediate 37 using the starting materials (SM) indicated.

Ex Compound Data SM 85 Methyl 2-((3R,4R)-4-{[(3,4- MS (ES) MH⁺: 447 for Intermediate 30 and dichloro-5-methyl-1H- C₁₇H₂₀ClN₄O₄S; NMR: 1.71 (m, 1H), Intermediate 1 pyrrol-2-yl)carbonyl]amino}-3- 1.93 (m, 1H), 2.18 (s, 3H), 3.24-3.28 (m, methoxypiperidin-1-yl)-1,3- 2H), 3.31 (s, 3H), 3.75 (s, 3H), 3.79 (m, thiazole-5-carboxylate 1H), 4.02-4.11 (m, 2H), 7.35 (d, 1H),

7.88 (s, 1H0, 12.00 (s, 1H) 86 Methyl 2-((35,4S)-4-{[(3,4- MS (ES) MH⁺: 447 for Intermediate 31 and dichloro-5-methyl-1H- C₁₇H₂₀ClN₄O₄S; NMR: 1.71 (m, Intermediate 1 pyrrol-2- 1H), 1.93 (m, 1H), 2.18 (s, 3H), yl)carbonyl]amino}-3- 3.24-3.28 (m, 2H), 3.31 (s, 3H), methoxypiperidin-1-yl)-1,3- 3.75 (s, 3H), 3.79 (m, 1H), 4.02- thiazole-5-carboxylate 4.11 (m, 2H), 7.35 (d, 1H), 7.88 (s, 1H0, 12.00 (s, 1H)

Preparation of Starting Materials for Examples 1-86 Intermediate 1 3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid

Ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 2; 7.765 g, 0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70° C. solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0° C. for 1 h, and a purple solid was filtered, washed with water and lyophilized overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product. MS (ES⁻): 192.13, 194.13 for C₆H₅Cl₂NO₂; NMR: 2.17 (s, 3H).

Intermediate 2 Ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate

Method 1

A solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 3; 7.00 g, 0.0457 mol) in tetrachloromethane (30 ml) was cooled to 0° C. under nitrogen. The rubber septum used in the apparatus was pierced with a needle, and SO₂Cl₂ (7.8 ml, 0.096 mol) was then added dropwise over 25 min. Within 1 h, the reaction mixture had formed a slurry. The solid was collected by suction filtration, washed with cold tetrachloromethane, and dried under vacuum overnight to give the title product as a peach coloured solid (7.84 g, 0.0353 mol, 77% yield). MS (ES): 222.00, 224.00 for C₈H₉Cl₂NO₂; NMR: 1.34-1.40 (t, 3H), 2.28 (s, 3H), 4.32-4.38 (m, 2H).

Method 2

A 4-neck 22 L round bottom flask equipped with an overhead stirrer, reflux condenser, nitrogen inlet and an internal temperature probe was charged with (Intermediate 253, 1000 g, 3.9 mol), 1-methyl-2-pyrrolidinone (10 L) and sodium cyanoborohydride (382 g, 6.1 mol, 1.56 eq). The resulting solution was heated at 75-80° C. for 6 h and allowed to cool to ambient overnight. Reaction solution was poured into water (20 L) resulting in a light brown suspension and product was extracted with methyl tert-butyl ether (2×10 L). Organic layer was dried with sodium sulfate and concentrated under reduced pressure to a thick slurry, which was filtered and solid dried in convection oven yielding 4 (518 g, 60%) as a light brown solid.

Intermediate 3 Ethyl 5-methyl-1H-pyrrole-2-carboxylate

Sodium (2.79 g, 0.121 mmol) was dissolved in anhydrous EtOH (100 ml), then 2,2,2-trichloro-1-(5-methyl-1H-pyrrol-2-yl)ethanone (Intermediate 4; 22.5 g, 0.099 mmol) was added in small portions. The dark brown solution was stirred at room temperature for 30 min then concentrated under vacuum to a small volume. The mixture was cooled in an ice bath and 3 N HCl was added slowly then extracted with diethyl ether (3×100 ml). The ether extracts were washed with 10% NaHCO₃, water and brine, dried over Na₂SO₄ and concentrated in vacuo to give the title compound as a brown solid. (15.04 g). NMR: 1.32 (t, 3H), 2.1 (s, 3H), 4.371 (q, 2H), 5.96 (dd, 1H), 6.78 (dd, 1H), 11.67 (s, 1H).

Intermediate 4 2,2,2-Trichloro-1-(5-methyl-1H-pyrrol-2-yl)ethanone

2-Methyl-1H-pyrrole (Intermediate 5; 10 g, 0.123 mmol) in anhydrous diethyl ether (30 ml) was added dropwise over 1 h to a stirred solution of triacetyl chloride (29 g, 0.16 mmol) in anhydrous Et₂O (100 ml). The mixture was stirred for a further 1 h then K₂CO₃ (10 g/30 ml) was added slowly through a dropping funnel. The organic phase was dried over Na₂SO₄ and treated with decolourizing charcoal (3 g) for 30 min at room temperature. The resulting purple solution was concentrated and triturated with n-hexanes to give the title compound as a purple solid. (16.72 g). NMR (CDCl₃): 2.36 (s, 3H), 6.04 (dd, 1H), 7.45 (dd, 1H), 10.344 (s, 1H).

Intermediate 5 2-Methyl-1H-pyrrole

Potassium hydroxide (50 g, 0.89 mmol) was added to a solution of ethylene glycol (750 ml) and 1H-pyrrole-2-carbaldehyde (50 g, 0.53 mmol). Hydrazine hydrate (37 ml, 0.745 mmol) was added slowly over 15 min. The reaction mixture was refluxed at 90° C. for 90 min. The mixture was cooled to room temperature and cold water (250 ml) was added. The aqueous mixture was extracted with DCM (250 ml). The organic phase was washed with water (250 ml), dried over Na₂SO₄ and concentrated in vacuo. Kugelrohr distillation gave the title compound as a clear colourless liquid (29.75 g). NMR: 2.1 (s, 3H), 5.77 (s, 1H), 5.9 (dd, 1H), 6.25 (dd, 1H), 10.54 (s, 1H).

Intermediate 6 4-Chloro-5-methyl-1H-pyrrole-2-carboxylic acid

Lithium hydroxide (2 M, 4 ml) was warmed to 50° C. and a solution of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7; 0.30 g, 1.60 mmol) in MeOH was added to it. The reaction was heated to 80° C. and stirred for two hours. The MeOH was removed and the aqueous solution was cooled to 0° C. and acidified with 30% HCl. The precipitated product (0.23 g, 92%) was filtered and dried. MS (ES): 160 (M+1) for C₆H₆ClNO₂; NMR (CDCl₃): 2.25 (s, 3H), 6.85 (s, 1H), 8.98 (brs, 1H).

Intermediate 7 Ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate

N-Chlorosuccinimide (0.67 g, 5.08 mmol) was added to a solution of ethyl 5 -methyl-1H-pyrrole-2-carboxylate (Intermediate 3; 0.65 g, 4.23 mmol) in chloroform (20 ml). The reaction was warmed to 40° C. and stirred for 4 h, then poured to a beaker containing 2 N NaOH (20 ml) at 0° C. The layers were separated and the aqueous layer was extracted with chloroform (×3). The combined organic extracts were dried over magnesium sulfate and concentrated. The resultant off-white solid was purified by flash chromatography (hexanes/EtOAc, 16:1) to give the title product as a white solid (0.3 g, 38%). MS (ES): 188 (M+1) for C₈H₁₀ClNO₂; NMR (CDCl₃): 1.34 (t, 3H), 2.27 (s, 3H), 4.30 (q, 2H), 6.76 (s, 1H), 9.07 (brs, 1H).

Intermediate 8 3,4-Difluoro-2-methyl-1H-pyrrole

BH₃THF (400 ml, 1M in THF) was added dropwise to a solution of 3, 4-difluoro-1H-pyrrole-2-carbaldehyde (Intermediate 19; 3.82 g) in THF (50 ml) cooled in an ice-water bath under N₂. The reaction mixture was stirred at room temperature for 3 days. MeOH was added slowly to quench excess of BH₃ and then the solvent was removed in vacuo at 0° C. The resulting yellow oil was triturated with hexanes/DCM and the yellow precipitate was removed by filtration. The filtrate was washed with NaHCO₃, H₂O and brine, dried over Na₂SO₄, filtered and concentrated at 0° C. in vacuo to give a pale yellow oil (3.8 g). MS (ES) MH⁺: 116 for C₅H₅F₂N; NMR (CDCl₃): 2.15 (s, 3H), 6.22 (m, 1H).

Intermediate 9 1-tert-Butyl-3-methyl-4-hydroxy-5,6-dihydropyridine-1,3-(2H)-dicarboxylate

Methyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate-hydrochloride (25 g) was suspended in DCM (250 ml). DIEA (41.6 g) was added in a single portion and the resultant homogeneous solution was cooled to 0° C. A DCM solution of di-tert-butyl dicarbonate (29.5 g, 1.05 moles) was added dropwise over a 1 h period. After the addition, the reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated to one-half the volume and washed with water, brine, dried over Na₂SO₄, filtered and concentrated in vacuo to an oil. The crude product was purified by flash column chromatography eluting with (20% EtOAc/80% hexanes) to give the title product (33 g). NMR (CDCl₃): 1.48 (s, 9H), 2.37 (m, 2H), 3.57 (t, 2H), 3.78 (s, 3H), 4.06 (brs, 2H), 11.9 (s, 1H).

Intermediate 10 Ethyl 4-chloroquinoline-2-carboxylate

Phosphorous oxychloride (5 ml) was added to ethyl 4-hydroxyquinoline-2-carboxylate (1.01 g). The reaction mixture was subjected to single-mode microwave at 100° C. for 30 min using a Smith Microwave Synthesizer. The solvent was removed in vacuo and recrystallized with acetone to gave the title compound as a white solid (1.90 g). MS (ES) MH⁺: 235, 237 for C₁₂H₁₀ClNO₂; NMR (CDCl₃): 1.44 (t, 3H, J=7.16), 4.51 (q, 2H, J=7.16), 7.19 (s, 1H), 7.71 (m, 1H), 7.81 (m, 1H), 8.22 (m, 1H), 8.36 (d, 1H, J=8.29).

Intermediate 11 2-(Methylthio)-1,3-thiazole-4-carboxylic acid

Ethyl 2-(methylthio)-1,3-thiazole-4-carboxylate (5.0 g) (Sinha, Subhash C et al. Tet. Lett. 2000, 41 (43), 8243-8246) was dissolved in MeOH (50 ml) and 2N LiOH (74 ml) was added. After stirring at room temperature for five minutes the reaction mixture was concentrated to remove MeOH and the residue was suspended in water and acidified with conc. HCl to pH 3. The white precipitate was filtered and dried to yield the title compound (3.42 g). NMR: 2.72 (s, 3H), 8.35 (s, 1H).

Intermediate 12 2-(Methylthio)-4-thiazolecarbonyl chloride

2-(Methylthio)-1,3-thiazole-4-carboxylic acid (Intermediate 11; 1.0 g) in thionyl chloride (10 ml) was heated to reflux for 30 min. The solution was cooled to room temperature and concentrated in vacuo. The residue was washed with anhydrous THF and concentrated to yield a black solid which was dried and stored cold under nitrogen (1.2 g). NMR (CDCl₃): 2.76 (s, 3H), 8.32 (s, 1H).

Intermediate 13 N-(1-Methyl-1-phenylethyl)-2-(methylthio)-1,3-thiazole-4-carboxamide

Triethylamine (2.24 ml) was added to a solution of cumylamine (3.2 ml) in anhydrous THF (30 ml). After stirring for 15 min, a solution of 2-(methylthio)-4 -thiazolecarbonyl chloride (Intermediate 12; 3.1 g) in anhydrous THF was added and the reaction mixture was concentrated in vacuo after 15 min. The residue was partitioned with EtOAc and water, dried with MgSO₄, and concentrated to an orange oil. Flash purification on silica gel with isocratic elution of DCM yielded the product as a yellow oil (3.7 g). MS (ES) MH⁺: 293 for C₁₄H₁₆N₂OS₂; NMR: 1.68 (s, 6H), 2.76 (s, 3H), 7.20 (d, J=7.16 Hz, 1H), 7.29 (t, J=7.54 Hz, 2H), 7.36-7.41 (m, 2H), 8.04 (s, 1H), 8.08 (s, 1H).

Intermediate 14 4-{[(1-Methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylic acid

Diisopropylamine (4.2 ml) was dissolve in anhydrous THF (100 ml) was cooled to −78° C. and to this was added n-butyl lithium (12 ml) slowly. The solution was slowly warmed to 0° C. and then cooled back to −78° C. A solution of N-(1 -methyl-1-phenylethyl)-2-(methylthio)-1,3-thiazole-4-carboxamide (Intermediate 13; 2.8 g) in anhydrous THF was added slowly maintaining the temperature below −70° C. After stirring for 30 min, a solution of methyl cyano formate (1.6 ml) in anhydrous THF was added in one portion and the reaction was stirred at −78° C. for 30 min followed by slow warming to room temperature. The reaction mixture was diluted with water and extracted with ether. The aqueous portion was acidified with conc. HCl, extracted with EtOAc, dried with MgSO₄ and concentrated to an orange solid (0.9 g). MS (ES) MH⁺: 337 for C₁₅H₁₆N₂O₃S₂; NMR: 1.66-1.74 (m, 6H), 2.80 (s, 3H), 7.23 (d, J=7.16 Hz, 1H), 7.33 (t, J=7.54 Hz, 2H), 7.45 (s, 2H), 9.07 (s, 1H).

Intermediate 15 Methyl 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2 -(methylthio)-1,3-thiazole-5-carboxylate

Potassium carbonate (0.37 g) and iodomethane (0.17 ml) were added to a solution of 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylic acid (Intermediate 14; 0.9 g) in DMF (20 ml) and heated in a sealed tube at an external temperature of 85° C. for 30 min. The reaction mixture was concentrated to remove DMF and partitioned with EtOAc and water. The combined organic extracts were washed with water, dried with MgSO₄, and concentrated to an orange solid (0.63 g). NMR: 1.60-1.65 (m, 6H), 2.76 (s, 3H), 3.78-3.83 (m, 3H), 7.22 (d, J=7.16 Hz, 1H), 7.33 (t, J=7.63 Hz, 2H), 7.46 (d, J=7.35 Hz, 2H), 8.75 (s, 1H).

Intermediate 16 Methyl 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylsulfonyl)-1,3-thiazole-5-carboxylate

3-Chloroperbenzoic acid (0.89 g) was added to a solution of methyl 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylate (Intermediate 15; 0.63 g) in DCM (25 ml). After stirring overnight the reaction was complete. Aqueous sodium bisulfite was added to quench any unreacted peroxides and the solution was washed with sat. NaHCO₃. The organic portion was dried with MgSO₄ and concentrated to a yellow solid (0.6 g). NMR: 1.63-1.68 (m, 6H), 3.58 (s, 3H), 3.89 (s, 3H), 7.23 (d, J=7.16 Hz, 1H), 7.34 (t, J=7.63 Hz, 2H), 7.47 (d, J=7.54 Hz, 2H), 8.91 (s, 1H).

Intermediate 17 Methyl-2-chloro-4-(methoxymethyl)-1,3-thiazole-5-carboxylate

tert-Butyl nitrite (2.2 ml, 18.6 mmol) and cuprous chloride (1.5 g) were suspended in anhydrous CH₃CN (100 ml). Methyl 2-amino-4-(methoxymethyl)-1,3-thiazole-5-carboxylate (2.5 g) prepared as described in (Kennedy, Alan R. et al. Acta Crystallographica, Section C: Crystal Structure Communications (1999, C55 (7) 2) was added in one portion. The mixture was stirred at room temperature for 2 h and the temperature was raised to 70° C. for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was poured into 6 N HCl, extracted with EtOAc, dried with MgSO₄ and concentrated to a black oil. Flash purification on silica gel with gradient elution (hexane to EtOAc) yielded product as a yellow liquid (0.82 g). NMR: 3.31 (s, 3H), 3.85 (s, 3H), 4.71 (s, 2H).

Intermediate 18 3,4-Difluoro-1H-pyrrole

3,4-Difluoro-1H-pyrrole was prepared as described in Eric K. Woller et al., J. Org. Chem., 1998 63(16), 5706-5707) and references therein. Thus, to a solution of 3,3,4,4-tetrafluoro-pyrrolidine hydrochloride (30.2 g) in dry DMSO (250 ml) cooled in an ice-water bath, t-BuOK was added (100 g) under N₂. After the addition was complete (˜0.5 h), the reaction mixture was stirred at room temperature for another 0.5 h. It was cooled to 0° C. and quenched with ice water (300 ml). After the solid dissolved, the mixture was diluted to ˜1.51 with water, neutralized to pH 7 with HCl, and extracted with DCM. The combined DCM extracts were washed with water, brine, dried over MgSO₄ and filtered. DCM was removed in vacuo at 0° C., and the resulting orange oil was dissolved in pentane at room temperature, cooled to −20° C. overnight and filtered under N₂ to give the title compound as golden crystals (4.6 g). NMR (CDCl₃): 6.38 (d, 1H), 6.41 (d, 1H).

Intermediate 19 3,4-Difluoro-1H-pyrrole-2-carbaldehyde

DMF (4.3 ml) was cooled in ice-water bath under N₂ and POCl₃ (5.2 ml) was added dropwise. The mixture was stirred at room temperature for 10 min. The ice-water bath was replaced, and the mixture was diluted with DCM (45 ml). A solution of 3,4-difluoro-1H-pyrrole (Intermediate 18; 4.57 g) in DCM (45 ml) was added dropwise. The mixture was refluxed for 30 min, cooled to room temperature and a solution of NaOAc (23 g) in water (60 ml) was added slowly. The resulting mixture was refluxed for 30 min, organic phase was separated and aqueous phase was extracted with DCM. The combined organic phase was washed with NaHCO₃, dried over Na₂SO₄, and concentrated in vacuo. The crude solid was triturated with DCM (20 ml)/pentane (100 ml), and then cooled to −20° C. to give the title compound as pale brown needles (4.73 g). NMR (CDCl₃): 6.87 (m, 1H), 9.6 (m, 1H).

Intermediate 20 3,4-Difluoro-5-methyl-1H-pyrrole-2-carboxylic acid

2,2,2-Trichloro-1-(3,4-difluoro-5-methyl-1H-pyrrol-2-yl)ethanone (Intermediate 80; 1.03 g) was added to an aqueous solution of NaOH (18 ml) at 0° C. under N₂. The mixture was stirred at room temperature for a further 2 h, cooled to 0° C. and acidified with HCl to ˜pH 2. A brown precipitate of product was collected by filtration. The crude product was purified by column chromatography on silica gel elution with EtOAc/hexanes (1:1). Trituration with DCM (1 ml)/pentane (6 ml) gave the title compound as a pale brown solid (306 mg). M.p. 140° C. (dec.). MS (ES) MH⁺: 160, 161 for C₆H₅F₂NO₂; NMR (CDCl₃): 2.15 (s, 3H), 11.5 (s, 1H), 12.8 (brs, 1H).

Intermediate 21 Cis(±)ethyl 4-amino-3-methoxypiperidine-1-carboxylate hydrochloride salt

The title compound can be prepared as described in Lee, C. et al. Synth. Comm. 2001, 31(7), 10881-10890 and/or WO 94/12494 or from Intermediate 157 by the following procedure;

To a stirred solution of the benzylamine (36.45 g, 125 mmol) and 10% palladium on activated carbon (50% wet; approximately 4 g) in methanol (250 mL), at room temperature and under an atmosphere of N₂, was added ammonium formate (31.50 g, 500 mmol) as a solid. Temperature was increased to 70° C.; the reaction was stirred overnight at this temperature, under an atmosphere of N₂. Complete conversion was suggested by TLC (6% methanol in ethyl acetate; Rf˜0.06 in a solution of 15% methanol and 30% acetone in methylene chloride) in the morning. The reaction mixture was filtered through Celite and concentrated under vacuum. To the residue was added approximately 50 mL water; from this mixture was extracted the crude product with a solution of ˜3% methanol in chloroform (4×300 mL). Organic layers were combined, dried over magnesium sulfate, and concentrated. Obtained 24.18 g (96%) of an off-white solid.

MS (ES) MH⁺: 202 for C₉H₁₈N₂O₃.

Intermediate 22 Cis(±)ethyl 4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate

Benzyl chloroformate (3.3 ml) was added dropwise to a cold solution of Cis(±)ethyl 4-amino-3-methoxypiperidine-1-carboxylate hydrochloride salt (Intermediate 21; 5 g) in saturated NaHCO₃. The mixture was stirred at room temperature for 14 h. The white precipitate was filtered, washed well with water, dried in vacuo to give the title compound as a white solid (6.66 g). MS (ES) MH⁺: 336 for C₁₇H₂₄N₂O₅; NMR: 1.21 (t, 3H), 1.52-1.67 (m, 2H), 3.08 (m, 2H), 3.28 (s, 3H), 3.41 (s, 2H), 3.74-3.92 (m, 2H), 3.96 (m, 2H), 4.14 (m, 1H), 5.10 (s, 2H), 7.24 (d, 1H), 7.44 (m, 5H).

Intermediate 23 and Intermediate 24 ethyl (3R,4S)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate and ethyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate

Cis(±)ethyl 4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate (Intermediate 22; 6.2 g) were separated into its enantiomers by chiral chromatography over a Chiralcel OJ column (eluant: hexanes/MeOH/EtOH; 70/15/15; 0.1% diethylamine). The fractions corresponding to the first chromatographic peak (Cis(−)isomer) were collected and evaporated yielding the title compound as a white solid (2.62 g). The fractions corresponding to the second chromatographic peak (Cis(+)isomer) were collected and evaporated yielding the title compound as a white solid (2.71 g). MS (ES)(M+Na)⁺: 360 for C₁₇H₂₄N₂O₅; NMR: 1.21 (t, 3H), 1.52-1.67 (m, 2H), 3.08 (m, 2H), 3.28 (s, 3H), 3.41 (s, 2H), 3.74-3.92 (m, 2H), 3.96 (m, 2H), 4.14 (m, 1H), 5.10 (s, 2H), 7.24 (d, 1H), 7.44 (m, 5H).

Intermediate 25 ethyl (3S,4R)-4-amino-3-methoxypiperidine-1-carboxylate

ethyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate (Intermediate 24; 3.98 g) was dissolved in MeOH (100 ml) and 1N HCl (50 ml). 10% Pd-charcoal (600 mg) was added, degassed and hydrogenolysed under an atmosphere of H₂ gas at room temperature for 3 h. The catalyst was filtered through a bed of celite, concentrated in vacuo and lyophilized giving the title compound (2.8 g). MS (ES) MH⁺: 202 for C₉H₁₈N₂O₃.

Intermediate 26

The following compound was prepared in a manner analogous to Intermediate 25 from the starting material indicated.

Int Compound MS SM 26 ethyl (3R,4S)-4-amino-3- MS (ES) MH⁺: 202 Intermediate methoxypiperidine-1-carboxylate for C₉H₁₈N₂O₃ 23

Intermediate 27 Cis(±)ethyl-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate

A 50% aqueous solution of sodium hydroxide (3 ml) was added to a suspension of allyl bromide (693 mg, 5.70 mmol), cis(±)ethyl 4-[(tert-butoxycarbonyl)amino]-3-hydroxypiperidine-1-carboxylate (reference: C. H. Lee et al. Syn. Commun., 2001, 31, 1081), (750 mg, 2.6 mmol), benzyltriethylammonium chloride (4 mg, cat.) and toluene (8 ml). The resultant mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (150 ml) and water (35 ml). The organic phase was separated and the aqueous phase was back extracted with EtOAc (2×30 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography (hexane/EtOAc, 3:2) to yield 734 mg of the title compound. MS (ES)(M+H): 329. for C₁₆H₂₈N₂O₅; NMR: 1.28 (t, 3H), 1.47 (s, 9H), 1.68 (m, 2H), 2.88 (brt, 2H), 3.50 (m, 1H), 3.68 (m, 1H), 3.90 (m, 1H), 4.00-4.45 (m, 3H), 4.10 (q, 2H), 4.92 (brs, 1H), 5.20 (m, 2H), 5.86 (m, 1H).

Intermediate 28 Cis(±)ethyl-3-(allyloxy)-4-amino]piperidine-1-carboxylate hydrochloride salt

4N HCl/dioxane (20 ml) was added to cis(±)ethyl-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (Intermediate 27; 572 mg). The mixture was stirred at room temperature for 90 min. The solvent was removed in vacuo, dried in vacuo to give the title compound as an oily foam which was used without further purification (449 mg). MS (ES)(M+H): 228. for C₁₁H₂₀N₂O₃.

Intermediates 29-36

The following compounds were prepared in a manner analogous to Intermediate 28 from the starting material (SM) indicated.

Int Compound Data SM 29 Cis(±)ethyl-4-amino-3- MS (ES)(M + H): 220 for Intermediate 81 propyoxypiperidine-1-carboxylate C₁₁H₂₂N₂O₃ hydrochloride salt 30 Methyl 2-[(3R,4R)-4-amino-3- methoxypiperidin-1-yl]-1,3-thiazole- 5-carboxylate hydrochloride salt

NMR: 1.63 (m, 1H), 2.08 (d, 1H), 2.97-3.01 (m, 1H), 3.21-3.24 (m, 2H), 3.25 (m, 2H), 3.40 (s, 3H), 3.73 (s, 3H), 3.88 (d, 1H), 4.34 (m, 1H), 7.87 (s, 1H), 8.28 (brs, 3H) Intermediate 68 31 Methyl 2-[(3S,4S)-4-amino-3- NMR: 1.63 (m, 1H), 2.08 (d, Intermediate 69 methoxypiperidin-1-yl]-1,3-thiazole- 1H), 2.97-3.01 (m, 1H), 5-carboxylate hydrochloride salt 3.21-3.24 (m, 2H), 3.25 (m, 2H), 3.40 (s, 3H), 3.73 (s, 3H), 3.88 (d, 1H), 4.34 (m, 1H), 7.87 (s, 1H), 8.28 (brs, 3H) 32 Cis(±)3,4-dichloro-N-[3- NMR: 1.92-1.96 (m, 2H), Intermediate 49 fluoropiperidin-4-yl]-5-methyl-1H- 2.20 (s, 3H), 3.10 (m, 1H), pyrrole-2-carboxamide 3.43-3.51 (m, 2H), 3.64 (m, hydrochloride salt 1H), 4.27-4.38 (m, 1H), 5.05 (d, 1H), 7.58 (d, 1H), 8.75 (brs, 1H), 9.43 (brs, 1H), 12.32 (s, 1H) 33 3,4-dichloro-N-[(3R,4S)-3- MS (ES) (M + H): 294, 296 Intermediate 45 fluoropiperidin-4-yl]-5-methyl-1H- for C₁₁H₁₄Cl₂FN₃O pyrrole-2-carboxamide hydrochloride 34 Trans(±)3,4-dichloro-N-[3- MS (ES) (M + H): 294, 296 Intermediate 44 fluoropiperidin-4-yl]-5-methyl-1H- for C₁₁H₁₄Cl₂FN₃O pyrrole-2-carboxamide hydrochloride 35 Cis(±)methyl 4-{[(3,4-dichloro-5- MS (ES) (M + H): 332 for Intermediate 46 methyl-1H-pyrrol-2- C₁₃H₁₇Cl₂N₃O₃ yl)carbonyl]amino}piperidine-3- carboxylate hydrochloride salt

36 3,4-dichloro-N-[(3S,4R)-3- MS (ES) M + H): 294, 296 for Intermediate 48 fluoropiperidin-4-yl]-5-methyl-1H- C₁₁H₁₄Cl₂FN₃O pyrrole-2-carboxamide hydrochloride

Intermediate 37 Cis(±)ethyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate

3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 1; 304 mg) was dissolved in anhydrous DMF. HATU (596 mg), HOAT (213 mg) and DIEA (274 μl) were added and stirred at ambient for 15 min. Cis(±)ethyl 4-amino-3-methoxypiperidine-1-carboxylate (Intermediate 21; 317 mg) was added and the mixture was stirred at ambient for 18 h. The mixture was diluted with EtOAc and washed with water, 1N HCl, bicarbonate buffer, water, brine and dried over Na₂SO₄. The solution was concentrated in vacuo to give the title compound as a brown solid (503 mg). MS (ES) MH⁺: 378, 380 for C₁₅H₂₁Cl₂N₃O₄; NMR: 1.29 (t, 3H), 1.79 (m, 2H), 2.27 (s, 3H), 3.12 (m, 2H), 3.30 (s, 3H), 3.37 (m, 1H), 3.83-4.16 (m, 5H), 7.25 (d, 1H), 12.23 (s, 1H).

Intermediates 38-49

The following compounds were prepared in a manner analogous to Intermediate 37 from the starting material (SM) indicated.

Int Compound Data SM 38 Cis(±)ethyl-4-{[(3,4-difluoro-5- MS (ES) MH⁺: 344 for Intermediate 20 methyl-1H-pyrrol-2- C₁₅H₂₁F₂N₃O₄; NMR: 1.3 (t, and Intermediate 21 yl)carbonyl]amino}-3- 3H), 1.69 (m, 2H), 2.21 (s, methoxypiperidine-1- 3H), 3.11 (m, 2H), 3.22 (s, carboxylate 3H), 3.39 (m, 2H), 3.85 (q, 2H), 4.41 (m, 1H), 6.83 (d, 1H), 11.54 (s, 1H) 39 ethyl (3S,4R)-4-{[(3,4-dichloro- MS (ES) MH⁺: 377 for Intermediate 25 5-methyl-1H-pyrrol-2- C₁₅H₂₁Cl₂N₃O₄; NMR: 1.32 and Intermediate 1 yl)carbonyl]amino}-3- (t, 3H), 1.74 (m, 2H), 2.31 (s, methoxypiperidine-1- 3H), 3.14 (m, 2H), 3.18-3.52 carboxylate (s, 3H), 3.75-4.44 (m, 5H), 7.30 (d, 1H), 12.39 (s, 1H) 40 ethyl (3R,4S)-4-{[(3,4-dichloro- MS (ES) MH⁺: 377 for Intermediate 26 5-methyl-1H-pyrrol-2- C₁₅H₂₁Cl₂N₃O₄; NMR: 1.32 and Intermediate 1 yl)carbonyl]amino}-3- (t, 3H), 1.74 (m, 2H), 2.31 (s, methoxypiperidine-1- 3H), 3.14 (m, 2H), 3.18-3.52 carboxylate (s, 3H), 3.75-4.44 (m, 5H),

7.30 (d, 1H), 12.39 (s, 1H) 41 Ethyl 4-{[(4-chloro-5-methyl- MS (ES) MH⁺: for Intermediate 21 1H-pyrrol-2- C₁₅H₂₂ClN₃O₄; NMR: 1.18 (t, and Intermediate 6 yl)carbonyl]amino}-3- J = 7.06 Hz, 3H), 1.48 (d, methoxypiperidine-1- J = 3.58 Hz, 1H), 1.75 (td, carboxylate J = 12.29, 7.82 Hz, 1H), 2.10- 2.18 (m, 3H), 2.95 (d, J = 13.38 Hz, 2H), 3.20-3.27 (m, 3H), 3.27-3.35 (m, 2H), 3.38 (s, 1H), 3.97-4.09 (m, J = 10.53, 7.08, 7.08, 3.39 Hz, 2H), 4.19 (s, 1H), 6.88 (d, J = 2.64 Hz, 1H), 7.62 (d, J = 7.91 Hz, 1H), 11.60 (s, 1H) 42 Cis(±)ethyl 3-(allyloxy)-4- MS (ES) MH⁺: 402, 404 for Intermediate 1 and {[(3,4-dichloro-5-methyl-1H- C₁₇H₂₃Cl₂N₃O₄ Intermediate 28 pyrrol-2- yl)carbonyl]amino}piperidine- 1-carboxylate 43 Cis(±)ethyl 4-{[(3,4-dichloro-5- MS (ES) MH⁺: 404, 406 for Intermediate 1 and methyl-1H-pyrrol-2- C₁₇H₂₅Cl₂N₃O₄ Intermediate 29 yl)carbonyl]amino}-3- propoxypiperidine-1- carboxylate 44 Trans(±)tert-butyl-4-{[(3,4- MS (ES) (M + Na): 416, 418 Intermediate 60 dichloro-5-methyl-1H-pyrrol-2- for C₁₆H₂₂Cl₂FN₃O₃ and Intermediate 1 yl)carbonyl]amino}-3- fluoropiperidine-1-carboxylate 45 tert-butyl (3R,4S)-4-{[(3,4- MS (ES) (M + Na): 416, 418 Intermediate 61 dichloro-5-methyl-1H-pyrrol-2- for C₁₆H₂₂Cl₂FN₃O₃ and Intermediate 1 yl)carbonyl]amino}-3- fluoropiperidine-1-carboxylate

 46, 1-tert-Butyl 3-methyl 4-{[(3,4- 46: MS (ES − (M + H)⁺): 434, Intermediate 70 47 dichloro-5-methyl-1H-pyrrol-2- 436 for C₁₈H₂₅Cl₂N₃O₅; NMR and Intermediate 1 yl)carbonyl]amino}piperidine- 1.45 (s, 9H), 2.16 (m, 1H), 1,3-dicarboxylate 2.27 (s, 3H), 2.55 (dt, 1H), Note for Examples 46 and 47: 2.93 (m, 1H), 3.09 (m, 2H), The resultant crude mixture 3.66 (s, 3H), 4.08 (m, 1H), dissolved in DCM, added to a 4.29 (m, 2H), 6.68 (d, 1H), silica gel column, and was 9.66 (s, 1H) purified using a gradient of 10- 47: MS (ES) MH)⁺: 434, 436 50% EtOAc in hexanes. The for C₁₈H₂₅Cl₂N₃O₅; NMR: recovered mixture of 1.44 (s, 9H), 1.75 (m, 1H), diastereomers were taken up in 2.09 (m, 1H), 2.26 (s, 3H), EtOAc (200 ml), heated to 2.86 (m, 1H), 2.98 (m, 1H), 50° C., and filtered. The solid 3.17 (dd, 1H), 3.71 (s, 3H), was washed with EtOAc and 4.04 (m, 1H), 4.44 (m, 2H), dried, to show a 90:10 cis:trans 7.57 (d, 1H), 9.53 (s, 1H) mixture of diastereomers (2.3 g, 30.6% yield) (Intermediate 46). The filtrate was then subjected to a recrystallisation using EtOAc and n-heptane, and a 90:10 trans:cis mixture (2.65 g, 35.3% yield) (Intermediate 47) was recovered. 48 tert-butyl (3S,4R)-4-{[(3,4- MS (ES) (M + Na): 416, 418 Intermediate 64 dichloro-5-methyl-1H-pyrrol-2- for C₁₆H₂₂Cl₂FN₃O₃ and Intermediate 1 yl)carbonyl]amino}-3- fluoropiperidine-1-carboxylate 49 Cis(±)tert-butyl-4-{[(3,4- NMR (CDCl₃): 1.47 (s, 9H), Intermediate 59 dichloro-5-methyl-1H-pyrrol-2- 1.84-1.88 (m, 2H), 2.28 (s, and Intermediate 1 yl)carbonyl]amino}-3- 3H), 2.76-3.02 (m, 2H), 4.11- fluoropiperidine-1-carboxylate 4.26 (m, 2H), 4.43-4.51 (m, 1H), 4.77 (d, 1H)

Intermediate 50 Cis(±)3,4-dichloro-N-(3-methoxypiperidin-4-yl)-5-methyl-1H-pyrrole-2-carboxamide

The title compound was prepared by the methods described below:

Method A

Cis(±)ethyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate (Intermediate 37; 503 mg) was dissolved in MeOH (30 ml). 1 M NaOH was added and the mixture was heated at 100° C. for 12 h. The reaction mixture was cooled to ambient and extracted with EtOAc, washed with water, dried over Na₂SO₄ and concentrated in vacuo to give the title compound as a brown oily gum which was used without further purification (336 mg).

Method B

Cis(±)ethyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate (Intermediate 37; 3.85 g) was suspended in anhydrous CH₃CN. Iodotrimethylsilane (2.2 ml) was added slowly. The reaction was heated to reflux for several hours until complete by LCMS. The crude reaction mixture was diluted with water and acidified with 1N HCl to pH 3. The solution was extracted with EtOAc. The aqueous layer was basified with 50% NaOH to pH 10. The aqueous layer as saturated with sodium chloride and extracted with THF, dried with MgSO₄ and concentrated to a tan solid (2.1 g). MH⁺: 306 for C₁₂H₁₇Cl₂N₃O₂; NMR: 1.61 (d, J=3.77 Hz, 2H), 1.76 (dt, J=6.50, 3.16 Hz, 1H), 2.16-2.20 (m, 3H), 2.56-2.69 (m, 2H), 2.90 (d, J=13.19 Hz, 1H), 3.18 (dd, J=13.75, 3.01 Hz, 1H), 3.30-3.35 (m, 3H), 3.56-3.64 (m, 1H), 4.04-4.15 (m, J=8.10, 7.72, 7.72, 3.01 Hz, 1H), 7.14 (d, J=8.29 Hz, 1H).

Intermediates 51-56

The following Intermediates were prepared as described by the general methods described in Intermediate 50 from the starting materials (SM) indicated.

Int Compound Data SM 51 3,4-dichloro-N-[(3S,4R)-3- M/z 306; 1.73 (m, 2H), 2.31 (s, 3H), 2.64 (m, Intermediate methoxypiperidin-4-yl]-5- 1H), 2.98 (m, 1H), 3.22 (m, 1H), 3.34 (m, 39 methyl-1H-pyrrole-2- 1H), 3.34 (s, 3H), 3.42 (m, 2H), 4.25 (m, carboxamide 1H), 7.31 (d, 1H). 52 3,4-dichloro-N-(3R,4S)[3- M/z 306; 1.73 (m, 2H), 2.31 (s, 3H), 2.64 (m, Intermediate methoxypiperidin-4-yl]-5- 1H), 2.98 (m, 1H), 3.22 (m, 1H), 3.34 (m, 40 methyl-1H-pyrrole-2- 1H), 3.34 (s, 3H), 3.42 (m, 2H), 4.25 (m, carboxamide 1H), 7.31 (d, 1H). 53 Cis(±)3,4-dichloro-5- M/z 334 Intermediate methyl-N-(3- 43 propoxypiperidin-4-yl)- 1H-pyrrole-2-carboxamide 54 Cis(±)3,4-dichloro-5- M/z 332 Intermediate methyl-N-(3- 42 allyoxypiperidin-4-yl)-1H- pyrrole-2-carboxamide 55 Cis(±)4-chloro-N-(3- M/z 272; 1.41 (s, 1H), 1.67 (s, 1H), 2.13 (s, Intermediate methoxypiperidin-4-yl)-5- 3H), 2.47 (s, 1H), 2.55 (s, 1H), 2.86 (s, 1H), 41 methyl-1H-pyrrole-2- 3.08 (d, J = 13.19 Hz, 1H), 3.25 (s, 3H), carboxamide 3.31 (s, 1H), 6.89 (d, J = 2.45 Hz, 1H), 7.52 (s, 1H), 11.59 (s, 1H) 56 Cis(±)3,4-difluoro-N-(3- M/z 273; 1.74 (m, 2H), 2.24 (s, 3H), 3.00 (m, Intermediate methoxypiperidin-4-yl)-5- 1H), 3.21 (m, 1H), 3.36 (s, 3H), 3.42 (m, 38 methyl-1H-pyrrole-2- 4H), 4.20 (brm, 1H), 6.74 (brm, 1H), carboxamide 11.60 (brs, 1H).

Intermediate 57 and Intermediate 58 tert-Butyl-(3S,4R)-4-(benzylamino)-3-fluoropiperidine-1-carboxylate and tert-Butyl-(3R,4S)-4-(benzylamino)-3-fluoropiperidine-1-carboxylate

Cis(±)tert-butyl-4-(benzylamino)-3-fluoropiperidine-1-carboxylate (Intermediate 82; 2.2 g) was separated into the title compounds using chiral HPLC, in a manner analogous to Intermediate 23 and Intermediate 24 over a Chiralpak AD column (eluent: hexanes/MeOH/EtOH; 90/2.5/2.5; 0.1% diethylamine). The fractions corresponding to the first chromatographic peak (Cis(+) isomer; Intermediate 57) were collected and evaporated yielding the title compound as a white solid (942 mg). The fractions corresponding to the second chromatographic peak (Cis(−) isomer; Intermediate 58) were collected and evaporated yielding the title compound as a white solid (980 mg). NMR (CDCl₃): 1.40 (s, 9H), 1.88 (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H).

Intermediate 59 Cis(±)tert-butyl-4-amino-3-fluoropiperidine-1-carboxylate

Cis(±)tert-butyl-4-(benzylamino)-3-fluoropiperidine-1-carboxylate (Intermediate 82; 711 mg), ammonium formate (582 mg), and 10% Pd/C (200 mg) in MeOH (10 ml) was heated to 50° C. for 1 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (503 mg, quantitative). NMR (CDCl₃): 1.40 (s, 9H), 1.88 (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H).

Intermediates 60-64

The following Intermediates were prepared by the procedure described in Intermediate 59 from the starting materials (SM) indicated.

Int Compound Data SM 60 Trans(±)tert-butyl-4-amino-3- NMR (CDCl₃): 1.38 (s, 9H), 1.88 Intermediate 65 fluoropiperidine-1-carboxylate (m, 2H), 2.87 (m, 2H), 3.59 (m,

2H), 3.77 (m, 1H), 4.66 (d, 1H) 61 tert-butyl (3R,4S)-4-amino-3- NMR (CDCl₃): 1.40 (s, 9H), Intermediate 58 fluoropiperidine-1-carboxylate 1.88 (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H) 62 tert-Butyl [(3R,4R)-3- NMR (CDCl₃): 1.45 (s, 9H), Intermediate 66 methoxypiperidin-4- 2.43 (m, 1H), 2.50-2.57 (m, yl]carbamate 1H), 2.59-2.66 (m, 1H), 2.89 (m, 1H), 3.01 (m, 1H), 3.24 (m, 1H), 3.41 (s, 3H), 3.67 (m, 1H), 4.71 (m, 1H) 63 tert-Butyl [(3S,4S)-3- NMR (CDCl₃): 1.45 (s, 9H), Intermediate 67 methoxypiperidin-4- 2.43 (m, 1H), 2.50-2.57 (m, yl]carbamate 1H), 2.59-2.66 (m, 1H), 2.89 (m, 1H), 3.01 (m, 1H), 3.24 (m, 1H), 3.41 (s, 3H), 3.67 (m, 1H), 4.71 (m, 1H) 64 tert-butyl (3S,4R)-4-amino-3- NMR (CDCl₃): 1.40 (s, 9H), 1.88 Intermediate 57 fluoropiperidine-1-carboxylate (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H)

Intermediate 65 Trans(±)tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate

The title compound was prepared as described in Monique B. van Neil et al. J. Med. Chem., 1999, 42, 2087-2104 and the references therein. NMR (CDCl₃): 1.40 (s, 9H), 1.88 (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H).

Intermediate 66 tert-Butyl [(3R,4R)-1-benzyl-3-methoxypiperidin-4-yl]carbamate

The title compound (150 mg) was prepared from tert-butyl [(3R,4R)-1-benzyl-3-hydroxypiperidin-4-yl]carbamate by the procedure described (for similar compounds) in Synth. Commun., 2001, 31, 1081-1089. NMR (CDCl₃): 1.44 (s, 9H), 1.97-2.11 (m, 3H), 2.68 (d, 1H), 3.07-3.12 (m, 2H), 3.36 (s, 3H), 3.41 (m, 1H), 3.52 (m, 2H), 4.51 (m, 1H), 7.23-7.32 (m, 5H).

Intermediate 67 tert-Butyl [(3 S,4 S)-1-benzyl-3-methoxypiperidin-4-yl]carbamate

The title compound (426 mg) was prepared from tert-butyl [(3S,4S)-1-benzyl-3-hydroxypiperidin-4-yl]carbamate by the procedure described (for similar compounds) in Synth. Commun., 2001, 31, 1081-1089. NMR (CDCl₃): 1.44 (s, 9H), 1.97-2.11 (m, 3H), 2.68 (d, 1H), 3.07-3.12 (m, 2H), 3.36 (s, 3H), 3.41 (m, 1H), 3.52 (m, 2H), 4.51 (m, 1H), 7.23-7.32 (m, 5H).

Intermediates 68-69

The following Intermediates were prepared by the procedure described in Example 1 from the starting materials (SM) indicated.

Int Compound Data SM 68 2-{(3R,4R)-4-[(tert- MS (ES) (M + Na): 394 for Intermediate 62 and Butoxycarbonyl)amino]-3- C₁₆H₂₅N₃O₅S; NMR (CDCl₃): methyl 2-bromo- methoxypiperidin-1-yl}-1,3- 1.46 (s, 9H), 1.66 (m, 1H), 1,3-thiazole-5- thiazole-5-carboxylate 1.89 (m, 1H), 2.29 (m, 1H), carboxylate 3.13-3.20 (m, 3H), 3.47 (s, 3H), 3.75 (m, 1H), 3.83 (s, 3H), 4.20 (m, 1H), 4.60 (brs, 1H), 7.85 (s, 1H) 69 2-{(3S,4S)-4-[(tert- MS (ES) (M + Na): 394 for Intermediate 63 and Butoxycarbonyl)amino]-3- C₁₆H₂₅N₃O₅S; NMR (CDCl₃): methyl 2-bromo- methoxypiperidin-1-yl}-1,3- 1.46 (s, 9H), 1.66 (m, 1H), 1,3-thiazole-5- thiazole-5-carboxylate 1.89 (m, 1H), 2.29 (m, 1H), carboxylate 3.13-3.20 (m, 3H), 3.47 (s, 3H), 3.75 (m, 1H), 3.83 (s, 3H), 4.20 (m, 1H), 4.60 (brs, 1H), 7.85 (s, 1H)

Intermediate 70 1-tert-Butyl-3-methyl-4-aminopiperidine-1,3-dicarboxylate

The title compound was prepared according to (Cordero, F. M et al. Gazz. Chim. Ital. 1997, 127, 25-29). Thus, 1-tert-butyl-3-methyl-4-hydroxy-5,6-dihydropyridine-1,3-(2H)-dicarboxylate (Intermediate 9; 33 g) and NH₄OAc (100 g) were dissolved in dry MeOH (250 ml). NaCNBH₃ (8.1 g) was added in three equal portions at 1 h intervals. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by GC/MS and additional NH₄OAc (2.5 equiv.) and NaCNBH₃ (0.25 equiv.) were added until reaction was completed. The reaction was cooled to −10° C. and acidified to pH=2 with concentrated HCl and solvent was removed in vacuo. The solid residue was dissolved in water, and extracted with Et₂O. The pH of the aqueous phase was adjusted to 8-9 with solid KOH, solution saturated with NaCl and extracted with EtOAc. The organic layer was dried over K₂CO₃, filtered and concentrate to an oil (25 g). GC/MS: 258 for C₁₂H₂₂N₂O₄.

Intermediate 71 Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(hydroxymethyl)piperidine-1-carboxylate

Cis(±)1-tert-butyl-3-methyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-piperidine-1,3-dicarboxylate (Intermediate 46; 4.26 g) and LiBH₄ (321 mg) were combined in dry THF (20 ml). MeOH (600 μl) was added in a single portion. The reaction was heated to reflux for 1 h. The mixture was cooled to room temperature, diluted with EtOAc and washed with 0.5% HCl. The organic layer was dried over Na₂SO₄, filtered and concentrated to a solid which was purified by flash column chromatography eluting with (60% EtOAc/40% hexanes), to yield title compound (3.11 g). MS (ES)(MH⁺): 406 for C₁₇H₂₅Cl₂N₃O₄; NMR (CDCl₃): 1.47 (s, 9H), 1.56 (m, 1H), 1.96 (m, 1H), 2.27 (s, 3H), 2.84 (m, 1H), 2.9 (m, 1H), 3.49 (m, 1H), 3.71 (m, 1H), 4.16 (m, 5H), 6.58 (d, 1H), 10.1 (brs, 1H).

Intermediate 72 Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate

Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 71; 1.46 g) was dissolved in dry pyridine (20 ml) and cooled to 0° C. Tosylchloride (822 mg) was added in a single portion. The reaction was allowed to slowly warm to room temperature and stirred overnight. The mixture was diluted with EtOAc and washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo. The foam was purified by flash column chromatography eluting with (40% EtOAc/60% hexanes) to give title compound (1.58 g). MS (ES)(MH⁺): 560 for C₂₄H₃₁Cl₂N₃O₆S; NMR (CDCl₃): 1.46 (brs, 11H), 1.89 (m, 1H), 1.98 (m, 1H), 2.31 (s, 3H), 2.35 (s, 3H), 2.8 (m, 2H), 3.96-4.23 (m, 4H), 6.4 (d, 1H), 7.19 (d, 2H), 7.68 (d, 2H), 10.3 (brs, 1H).

Intermediate 73 Cis(±)4-[(3,4-Dichloro-5-methyl-1H-pyrrole-2-carbonyl) -amino]-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester

Cis-tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 72; 325 mg) was dissolved in 5 ml of a 30 wt % MeOH solution containing NaOMe and an additional 5 ml of dry MeOH. The homogeneous reaction was stirred at room temperature for 2 days. Upon reacting, solids began to precipitate from solution. The reaction was concentrated to a solid residue, re-dissolved in EtOAc and washed with saturated NH₄Cl (2×10 ml). The organic layer was dried over Na₂SO₄, filtered and concentrated. The residual material was purified by flash column chromatography eluting with (1:1 EtOAc/hexanes) to give the title compound (192 mg). MS (ES)(MH⁺): 420 for C₁₉H₂₇Cl₂N₃O₄.

Intermediate 74 Cis(±)3,4-dichloro-N-[3-(methoxymethyl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide hydrochloride

Cis(±)tert-butyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(methoxymethyl)piperidine-1-carboxylate (Intermediate 73; 192 mg, 0.45 mmol) was dissolved in 4N HCl in dioxane (10 ml) and 10 ml of MeOH. The mixture was stirred at room temperature for 3 h, concentrated to dryness and azeotroped with MeOH to remove excess HCl (5×20 ml) to yield the title compound which was used without purification. (crude mixture 195 mg). MS (ES)(MH⁺): 320 for C₁₃H₁₉Cl₂N₃O₂.

Intermediates 75-76

The following Intermediates were prepared by the procedure described in Intermediate 74 from the starting materials (SM) indicated.

Int Compound Data SM 75 Cis(±)3,4-Dichloro-5-methyl-1H-pyrrole-2- MS (ES) MH⁺: 319 for Intermediate carboxylic acid (3-methylaminomethyl- C₁₃H₂₀Cl₂N₄O 77 piperidin-4-yl)-amide hydrochloride

76 Cis-3,4-dichloro-5-methyl-1H-pyrrole-2- MS (ES) MH⁺: 333 for Intermediate carboxylic acid (3-dimethylaminomethyl- C₁₄H₂₂Cl₂N₄O 78 piperidin-4-yl)-amide hydrochloride

Intermediate 77 Cis(±)4-[(3,4-Dichloro-5-methyl-1H-pyrrole-2-carbonyl) -amino]-3-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester

Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-piperidine-1-carboxylate (Intermediate 72; 500 mg, 0.89 mmol) was dissolved in 5 ml of a 2.0 M THF solution containing MeNH₂. The reaction vessel was sealed and heated to 100° C. for 2 h. The mixture was cooled to room temperature and diluted with EtOAc, then washed with water. The organic layer was dried over Na₂SO₄, filtered and concentrated to a crude solid foam which was used without further purification. MS (ES)MH⁺: 419 for C₁₈H₂₈Cl₂N₄O₃.

Intermediate 78

The title compound was prepared in a manner analogous to Intermediate 77 from the starting material indicated.

Int Compound MS SM 78 Cis(±)4-[(3,4-Dichloro-5- MS (ES) MH⁺: Intermediate 72 methyl-1H-pyrrole-2-carbonyl)- 433 for and amino]-3- C₁₉H₃₀Cl₂N₄O₃ dimethylamine dimethylaminomethyl- piperidine-1-carboxylic acid tert-butyl ester

Intermediate 79 Cis(±)4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-3-carboxylic acid hydrochloride

THF (10 ml) and MeOH (8 ml) were added to cis(±)1-tert-butyl 3-methyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1,3-dicarboxylate (Intermediate 46; 2.24 g). The resultant mixture was cooled to 0° C., and a solution of lithium hydroxide (0.37 g) in water (5 ml) at 0° C. was added dropwise via pipette, producing a clear, lightly yellow solution. The reaction was stirred at 0° C. for 2 h, stored overnight in a freezer without stirring, then stirred again at 0° C. for six hours. The reaction was acidified to pH 3 with 2N HCl 9-7 ml), and was concentrated in vacuo. The resultant mixture was dissolved in EtOAc (125 ml) and a saturated aqueous sodium chloride solution (40 ml), followed by the addition of 2N HCl (˜1 ml) to acidify the aqueous layer to pH 1. The phases were separated and the aqueous layer was washed with EtOAc (2×60 ml). The combined EtOAc layers were dried over anhydrous MgSO₄ and concentrated in vacuo. The resultant white solid was suspended in anhydrous THF (35 ml) under an argon atmosphere, cooled to 0° C., followed by the addition of 4 M HCl in 1,4-dioxane (10 ml, 40 mmol). The reaction was warmed to room temperature, producing a clear orange-red solution. The reaction was stirred overnight at room temperature, followed by the addition of 5 ml of 4 M HCl in 1,4-dioxane. The reaction was stirred for two days at room temperature, then heated to 50° C. for two hours, and allowed to slowly cool to room temperature overnight. The reaction was concentrated in vacuo, and carried on to the next reaction without further purification (5.16 mmol). MS (ES)(M+H)): 320, 322 for C₁₂H₁₅Cl₂N₃O₃.

Intermediate 80 2,2,2-Trichloro-1-(3,4-difluoro-5-methyl-1H-pyrrol-2-yl)ethanone

3,4-Difluoro-2-methyl-1H-pyrrole (Intermediate 8; 3.8 g) was dissolved in anhydrous diethyl ether (100 ml). Anhydrous K₂CO₃ (12.5 g) was added followed by trichloroacetyl chloride (10 ml). The mixture was stirred at room temperature under N₂ for 2 h, poured into a cold saturated solution of NaHCO₃, stirred for 10 min, and extracted with ether. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give a red brown oil. Trituration with pentane (50 ml)/DCM (2 ml), at −20° C. overnight to gave the title compound as a brown powder (1.3 g). MS (ES) MH⁺: 262 for C₇H₄Cl₃F₂NO; NMR (CDCl₃): 2.35 (d, 3H), 9.0 (brs, 1H).

Intermediate 81 Cis(±)ethyl-4-[(tert-butoxycarbonyl)amino]-3-(propoxypiperidine-1-carboxylate

Cis(±)ethyl-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (Intermediate 27; 528 mg) was dissolved in MeOH (20 ml). 10% Pd—C (100 mg) was added and the mixture was evacuated and replaced with H₂ gas twice. The mixture was stirred under an atmosphere of H₂ gas for 12 h. The catalyst was removed over a bed of celite and solvent was removed in vacuo to give the title compound as an oil (445 mg). NMR: 0.94 (m, 3H), 1.25 (m, 3H), 1.43 (s, 9H), 1.53 (m, 2H), 1.71 (m, 1H), 3.04 (m, 2H), 3.37 (m, 2H), 3.50 (m, 2H), 3.69 (m, 1H), 3.89 (m, 1H), 4.15 (m, 2H), 6.5 (d, 1H).

Intermediate 82 Cis(±)tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate

The title compound was prepared as described in Monique B. van Neil et al. J. Med. Chem., 1999, 42, 2087-2104 and the references therein. NMR (CDCl₃): 1.40 (s, 9H), 1.88 (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H).

Examples 87-193

The following Examples were prepared by the procedure described in Example 1 from the starting materials (SM) indicated.

Ex Compound Data SM 87 Cis(±)-methyl 2-[4-{[(3,4- MS (ES) MH⁺: 447, 449 for Intermediate 115 and dichloro-5-methyl-1H-pyrrol-2- C₁₇H₂₀Cl₂N₄O₄S. methyl 2-bromo- yl)carbonyl]amino}-3- 1,3-thiazole-5- (hydroxymethyl)piperidin-1-yl]- carboxylate 1,3-thiazole-5-carboxylate. 88 Cis(±)-methyl 2-{4-{[(3,4- MS (ES) MH⁺: 477, 479 for Intermediate 116 and dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₂Cl₂N₄O₃S₂. methyl 2-bromo- yl)carbonyl]amino}-3- 1,3-thiazole-5- [(methylthio)methyl]piperidin- carboxylate 1-yl}-1,3-thiazole-5- carboxylate. 89 Cis(±)-methyl 2-{4-{[(3,4- MS (ES) MH⁺: 493, 495 for Example 88 and dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₂Cl₂N₄O₄S₂. methyl 2-bromo- yl)carbonyl]amino}-3- 1,3-thiazole-5- [(methylsulfinyl)methyl]piperidin- carboxylate 1-yl}-1,3-thiazole-5- carboxylate 90 Cis(±)-methyl 2-{4-{[(3,4- MS (ES) MH⁺: 509, 511 for Example 88 and dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₂Cl₂N₄O₅S₂. methyl 2-bromo- yl)carbonyl]amino}-3- 1,3-thiazole-5- [(methylsulfonyl)methyl]piperidin- carboxylate 1-yl}-1,3-thiazole-5-carboxylate

91 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 463, 465 for Intermediate 36 and dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₁Cl₂FN₄O₃S. Intermediate 179 yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-5-methyl- 1,3-thiazole-4-carboxylate. 92 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 475, 477 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₄Cl₂N₄O₄S. Intermediate 179 yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-5- methyl-1,3-thiazole-4-carboxylate 93 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 477, 479 for Intermediate 36 and dichloro-5-methyl-1H-pyrrol-2- C₁₈H₁₉Cl₂FN₄O₄S. Intermediate 181 yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-5-formyl- 1,3-thiazole-4-carboxylate 94 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 506, 508 for Intermediate 93 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₂Cl₂FN₅O₄S; ¹H NMR methoxyamine yl)carbonyl]amino}-3- (CDCl₃): 1.41 (m, 6H), 2.0 hydrochloride fluoropiperidin-1-yl)-5- (m, 4H), 2.3 (s, 6H), 3.2 (m, [(methoxyimino)methyl]-1,3- 4H), 3.9 (s, 3H), 4.0 (s, 3H), thiazole-4-carboxylate 4.4 (m, 10H), 4.8 (s, 1H), 4.9 (s, 1H), 7.0 (s, 2H), 8.5 (s, 1H), 8.8 (s, 1H), 9.6 (s, 2H) 95 Cis(±)-methyl 2-[(-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- (methylthio)piperidin-1-yl]-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 463.1 for C₁₇H₂₀Cl₂N₄O₃S₂; NMR: 1.90 (m, 2H); 2.14 (s, 3H); 2.28 (s, 3H); 3.28-3.45 (m, 2H); 3.74 (s, 3H); 3.77 (m, 1H); 3.95 (m, 2H); 4.44 (m, 1H); 7.25 (d, 1H); 7.85 (s, 1H); 12.14 (s, 1H) Intermediate 117 and Intermediate 1 96 Cis(±)-methyl 2-[4-{[(3,4- MS (ES) MH⁺: 495 for Intermediate 95 dichloro-5-methyl-1H-pyrrol-2- C₁₇H₂₀Cl₂N₄O₅S₂; NMR: yl)carbonyl]amino}-3- 1.88 (m, 2H); 2.18 (s, 3H); (methylsulfonyl)piperidin-1-yl]- 3.07 (s, 3H); 3.45 (t, 1H); 1,3-thiazole-5-carboxylate 3.61 (t, 1H); 3.60-3.85 (m, 2H); 3.77 (s, 3H); 4.48 (m, 1H); 4.68 (m, 1H); 7.52 (d, 1H); 7.93 (s, 1H); 12.07 (s, 1H) 97 Cis(±)methyl 2-(3-(benzyloxy)- MS (ES) MH⁺: 523 for Intermediate 118 4-{[(3,4-dichloro-5-methyl-1H- C₂₃H₂₄Cl₂N₄O₄S; NMR: and methyl 2- pyrrol-2- 1.73 (m, 2H); 2.12 (s, 3H); bromo-1,3-thiazole- yl)carbonyl]amino}piperidin-1- 3.36 (m, 2H); 3.68 (s, 3H); 5-carboxylate yl)-1,3-thiazole-5-carboxylate 3.71 (m, 2H); 3.90 (m, 1H); 4.25 (m, 1H), 4.40 (d, 1H), 4.65 (d, 1H); 7.02 (d, 1H); 7.19 (s, 5H); 7.79 (s, 1H); 12.06 (s, 1H) 98 Cis(±)-methyl 2-[4-{[(3,4- MS (ES) MH⁺: 471 for Intermediate 119 dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₀Cl₂N₄O₄S; NMR: and methyl-2- yl)carbonyl]amino}-3-(prop-2- 1.76 (m, 2H); 2.18 (s, 3H); bromo-1,3-thiazole- yn-1-yloxy)piperidin-1-yl]-1,3- 3.36 (m, 2H); 3.44 (t, 1H); 5-carboxylate thiazole-5-carboxylate 3.74 (s, 3H); 3.87 (s, 1H); 3.98 (m, 1H); 4.22-4.36 (m, 4H); 7.15 (d, 1H); 7.83 (s, 1H); 12.15 (s, 1H) 99 Trans-(±)methyl 2-(4-{[(3,4- MS (ES) MH⁺: 433 for Intermediate 120 dichloro-5-methyl-1H-pyrrol-2- C₁₆H₁₈Cl₂N₄O₄S; NMR: and methyl 2- yl)carbonyl]amino}-3- 1.62 (m, 1H), 2.02 (m, 1H), bromo-1,3-thiazole- hydroxypiperidin-1-yl)-1,3- 2.18 (s, 3H), 3.12 (m, 1H), 5-carboxylate thiazole-5-carboxylate 3.63 (m, 1H), 3.75 (s, 3H), 3.87 (m, 2H), 4.02 (m, 1H), 5.37 (d, 1H), 5.76 (s, 1H), 7.19 (d, 1H), 7.87 (s, 1H), 11.99 (s, 1H) 100 methyl 2-((3S,4R)-4-{[(3- chloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylate

1.87 (m, 2H); 2.17 (s, 3H); 3.34 (m 1H); 3.60 (m 1H); 3.75 (s, 3H); 4.01 (m, 1H); 4.33 (m, 2H); 4.96 (d, br, 1H); 5.95 (s, 1H); 7.10 (d, 1H); 7.85 (s, 1H); 11.63 (s, 1H) Intermediate 121 and methyl 2- bromo-1,3-thiazole- 5-carboxylate 101 ethyl 2-((3S,4R)-4-{[(3-chloro- 1.37 (t, 3H); 2.00 (m, 2H); Intermediate 121 5-methyl-1H-pyrrol-2- 2.26 (s, 3H); 3.31 (m 2H); and ethyl 2-bromo- yl)carbonyl]amino}-3- 4.21 (m, 1H); 4.34 (q, 2H); 1,3-thiazole-4- fluoropiperidin-1-yl)-1,3- 4.45 (m, 2H); 4.90 (d, br, carboxylate thiazole-4-carboxylate 1H); 5.93 (s, 1H); 6.97 (d, 1H); 7.46 (s, 1H); 8.98 (s, br, 1H) 102 ethyl 2-((3S,4R)-4-{[(3-chloro- MS (ES) MH⁺: 465 for Intermediate 121 5-methyl-1H-pyrrol-2- C₂₁H₂₂ClFN₄O₃S and ethyl 2-bromo- yl)carbonyl]amino}-3- NMR δ: 1.44 (t, 3H); 2.03 1,3-benzothiazole- fluoropiperidin-1-yl)-1,3- (m, 2H); 2.27 (s, 3H); 3.40 7-carboxylate benzothiazole-7-carboxylate (m 2H); 4.36 (m, 2H); 4.44 (q, 2H); 4.67 (m, 1H); 4.90 (d, br, 1H); 5.93 (s, 1H); 7.05 (d, 1H); 7.37 (t, 1H); 7.71 (d, 1H); 7.79 (d, 1H); 9.89 (s, br, 1H) 103 methyl 2-((3S,4R)-4-{[(4- MS (ES) MH⁺: 446 for Intermediate 122 bromo-5-methyl-1H-pyrrol-2- C₁₆H₁₈BrFN₄O₃S; NMR: and methyl 2- yl)carbonyl]amino}-3- 1.97 (m, 2H); 2.23 (s, 3H); bromo-1,3-thiazole- fluoropiperidin-1-yl)-1,3- 3.34 (m 2H); 3.80 (s, 3H); 5-carboxylate thiazole-5-carboxylate 4.26 (m, 2H); 4.55 (m, 1H); 4.86 (d, br, 1H); 6.0 (d, 1H); 6.53 (s, 1H); 7.82 (s, 1H); 9.83 (s, br, 1H) 104 methyl 2-((3S,4R)-4-{[(4- MS (ES) MH⁺: 480 for Intermediate 123 bromo-3-chloro-5-methyl-1H- C₁₆H₁₇BrClFN₄O₃S; NMR and methyl 2- pyrrol-2-yl)carbonyl]amino}-3- δ: 1.86 (m, 2H); 2.19 (s, bromo-1,3-thiazole- fluoropiperidin-1-yl)-1,3- 3H); 3.44 (m 1H); 3.60 (m 5-carboxylate thiazole-5-carboxylate 1H); 3.75 (s, 3H); 4.01 (m, 1H); 4.33 (m, 2H); 4.96 (d, br, 1H); 7.28 (d, 1H); 7.85 (s, 1H); 12.18 (s, 1H) 105 ethyl 2-((3S,4R)-4-{[(4-bromo- 3-chloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-4-carboxylate

MS (ES) MH⁺: 494 for C₁₇H₁₉BrClFN₄O₃S; NMR δ: 1.22 (t, 3H); 1.81 (m, 2H); 2.15 (s, 3H); 3.41 (m 2H); 3.90 (m, 1H); 4.20 (q, 2H); 4.30 (m, 1H); 4.92 (d, br, 1H); 5.72 (s, 1H); 7.24 (d, 1H); 7.65 (s, 1H); 12.13 (s, 1H) Intermediate 123 and ethyl 2-bromo- 1,3-thiazole-4- carboxylate 106 isopropyl 2-((3S,4R)-4-{[(4- 1.32 (d, 6H); 1.80 (m, 2H); Intermediate 123 bromo-3-chloro-5-methyl-1H- 2.19 (s, 3H); 3.07 (m 1H); and isopropyl 2- pyrrol-2-yl)carbonyl]amino}-3- 3.27 (m, 1H); 4.37 (m, 2H); bromo-isonicotinate fluoropiperidin-1- 4.71 (m, 1H); 4.97 (d, br, yl)isonicotinate 1H); 5.15 (m, 1H); 6.70 (d, 1H), 7.22 (d, 1H), 7.25 (s, 1H); 8.17 (d, 1H); 12.11 (s, br, 1H) 107 methyl 2-((3S,4R)-4-{[(4- MS (ES) MH⁺: 524 for Intermediate 123 bromo-3-chloro-5-methyl-1H- C₁₈H₂₁BrClFN₄O₄S; NMR and Intermediate 17 pyrrol-2-yl)carbonyl]amino}-3- δ: 1.86 (m, 2H); 2.19 (s, fluoropiperidin-1-yl)-4- 3H); 3.29 (s, 2H); 3.60 (m (methoxymethyl)-1,3-thiazole- 2H); 3.73 (s, 3H); 4.04 (m, 5-carboxylate 1H); 4.30 (m, 2H); 4.57 (s, 3H); 4.90 (d, br, 1H); 7.27 (d, 1H); 12.17 (s, 1H) 108 ethyl 2-((3S,4R)-4-{[(3-chloro- MS (ES) MH⁺: 409 for Intermediate 121 5-methyl-1H-pyrrol-2- C₁₉H₂₂ClFN₄O₃ and ethyl 2-bromo- yl)carbonyl]amino}-3- NMR: 1.40 (t, 3H); 1.98 (m, isonicotinate fluoropiperidin-1- 2H); 2.27 (s, 3H); 3.09 (m yl)isonicotinate 2H); 4.38 (q, 2H); 4.47 (m, 2H); 4.84 (m, 1H); 4.90 (d, br, 1H); 5.92 (s, 1H); 7.03 (d, 1H); 7.15 (d, 1H); 7.30 (s, 1H); 8.27 (d, 1H); 9.88 (s, br, 1H) 109 ethyl 2-((3S,4R)-4-{[(4-bromo- MS (ES) MH⁺: 409 for Intermediate 122 5-methyl-1H-pyrrol-2- C₁₉H₂₂BrFN₄O₃ and ethyl 2-bromo- yl)carbonyl]amino}-3- NMR: 1.40 (t, 3H); 1.98 (m, isonicotinate fluoropiperidin-1- 2H); 2.27 (s, 3H); 3.09 (m yl)isonicotinate 2H); 4.38 (q, 2H); 4.43 (m, 2H); 4.84 (m, 1H); 4.90 (d, br, 1H); 6.16 (d, 1H); 6.59 (s, 1H); 7.15 (d, 1H); 7.29 (s, 1H); 8.27 (d, 1H); 9.76 (s, br, 1H) 110 Cis(±)-Methyl 2-[4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3-(2- methoxyethoxy)piperidin-1-yl]- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 491 for C₁₉H₂₄Cl₂N₄O₅S; NMR: 1.72-1.80 (m, 2H), 2.17 (s, 3H), 3.13 (s, 3H), 3.25-3.42 (m, 4H), 3.52-3.60 (m, 1H), 3.65-3.75 (m, 2H), 3.73 (s, 3H); 3.85-4.05 (m, 1H); 4.20-4.35 (m, 2H), 7.14 (d, 1H), 7.82 (s, 1H), 12.14 (brs, 1H) Intermediate 124 and methyl 2-bromo- 1,3-thiazole-5- carboxylate 111 Cis(±)-Ethyl 2-[4-{[(3,4- MS (ES) MH⁺: 505 for Intermediate dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₆Cl₂N₄O₅S 124 and yl)carbonyl]amino}-3-(2- ethyl 2-bromo-1,3- methoxyethoxy)piperidin-1-yl]- thiazole-4- 1,3-thiazole-4-carboxylate carboxylate 112 Cis(±)-Ethyl 2-[4-{[(3,4- MS (ES) MH⁺: 519 for Intermediate dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₈Cl₂N₄O₅S; NMR: 124 and yl)carbonyl]amino}-3-(2- 1.22 (t, 3H), 1.70-1.75 (m, ethyl 2-chloro-1,3- methoxyethoxy)piperidin-1-yl]- 2H), 2.17 (s, 3H), 2.41 (s, thiazole-5- 4-methyl-1,3-thiazole-5- 3H), 3.14 (s, 3H), 3.32-3.40 carboxylate carboxylate (m, buried under water peak), 3.45-3.62 (m, 1H), 3.67-3.73 (m, 2H), 3.86-3.98 (m, 1H), 4.16 (q, 2H), 4.19- 4.30 (m, 2H), 7.13 (d, 1H), 12.14 (s, 1H) 113 Cis(±)-Ethyl 2-[4-{[(3,4- MS (ES) MH⁺: 499 for Intermediate 124 dichloro-5-methyl-1H-pyrrol-2- C₂₂H₂₈Cl₂N₄O₅ and ethyl 2- yl)carbonyl]amino}-3-(2- fluoroisonicotinate methoxyethoxy)piperidin-1- (Konno, Akinori J. yl]isonicotinate Fluorine Chemistry (1998), 87(2), 137- 140) 114 Cis(±)-Ethyl 2-[4-{[(3,4- MS (ES) MH⁺: 555 for Intermediate 124 dichloro-5-methyl-1H-pyrrol-2- C₂₄H₂₈Cl₂N₄O₅S and ethyl 2-bromo- yl)carbonyl]amino}-3-(2- 1,3-benzothiazole- methoxyethoxy)piperidin-1-yl]- 7-carboxylate 1,3-benzothiazole-7-carboxylate 115 Methyl 2-((3S,4R)-4-{[(4- chloro-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 387 for C₁₅H₁₆ClFN₄O₃S; NMR: 1.55-1.76 (m, 1H), 1.85-2.00 (m, 1H), 3.36-3.45 (m, 1H), 3.50 (dd, 1H), 3.74 (s, 3H), 4.02-4.10 (m, 1H), 4.15-4.36 (m, 2H), 4.90 (d, 1H), 6.94- 6.97 (m, 2H), 7.85 (s, 1H), 8.10 (d, 1H), 11.82 (s, 1H) Intermediate 95 and methyl 2-bromo- 1,3-thiazole-5- carboxylate 116 Ethyl 2-((3S,4R)-4-{[(4-chloro- MS (ES) MH⁺: 429 for Intermediate 260 5-methyl-1H-pyrrol-2- C₁₈H₂₂ClFN₄O₃S; NMR: and ethyl 2-chloro- yl)carbonyl]amino}-3- 1.23 (t, 3H), 1.62-1.77 (m, 4-methyl-1,3- fluoropiperidin-1-yl)-4-methyl- 1H), 1.83-2.00 (m, 1H), 2.13 thiazole-5- 1,3-thiazole-5-carboxylate (s, 3H), 2.43 (s, 3H), 3.33- carboxylate 3.41 (m, 1H), 3.50 (dd, 1H), 3.98-4.02 (m, 1H), 4.16 (q, 2H), 4.23-4.35 (m, 2H), 4.86 (d, 1H), 6.89 (d, 1H), 7.97 (d, 1H), 11.65 (s, 1H) 117 Ethyl 2-((3S,4R)-4-{[(4-chloro- MS (ES) MH⁺: 415 for Intermediate 95 1H-pyrrol-2- C₁₇H₂₀ClFN₄O₃S; NMR: ethyl 2-chloro-4- yl)carbonyl]amino}-3- 1.23 (t, 3H), 1.69-1.74 (m, methyl-1,3-thiazole- fluoropiperidin-1-yl)-4-methyl- 1H), 1.86-2.03 (m, 1H), 2.43 5-carboxylate 1,3-thiazole-5-carboxylate (s, 3H), 3.27-3.35 (m, 1H), 3.51 (dd, 1H), 3.98-4.05 (m, 1H), 4.16 (q, 2H), 4.23-4.33 (m, 2H), 4.88 (d, 1H), 6.94- 6.98 (m, 2H), 8.85 (d, 1H), 11.81 (s, 1H) 118 Ethyl 2-((3S,4R)-4-{[(4,5- MS (ES) MH⁺: 449 for Intermediate dichloro-1H-pyrrol-2- C₁₇H₁₉Cl₂FN₄O₃S; NMR: 128 and ethyl 2- yl)carbonyl]amino}-3- 1.23 (t, 3H), 1.65-1.74 (m, chloro-4-methyl- fluoropiperidin-1-yl)-4-methyl- 1H), 1.85-2.00 (m, 1H), 1,3-thiazole-5- 1,3-thiazole-5-carboxylate 2.43 (s, 3H), 3.30-3.40 (m, carboxylate 1H), 3.51 (dd, 1H), 3.98- 4.05 (m, 1H), 4.16 (q, 2H), 4.21-4.35 (m, 2H), 4.88 (d, 1H), 7.06 (d, 1H), 8.15 (d, 1H), 12.78 (s, 1H) 119 Methyl 2-((3S,4R)-4-{[(4,5- MS (ES) MH⁺: 421 for Intermediate dichloro-1H-pyrrol-2- C₁₅H₁₅Cl₂FN₄O₃S 128 and methyl 2- yl)carbonyl]amino}-3- bromo-1,3-thiazole- fluoropiperidin-1-yl)-1,3- 5-carboxylate thiazole-5-carboxylate 120 Cis(±)-Methyl 2-[4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3-(2- hydroxypropoxy)piperidin-1- yl]-1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 491 for C₁₉H₂₄Cl₂N₄O₅S; NMR: 0.95 (d, 3H), 1.75-1.90 (m, 2H), 2.17 (s, 3H), 3.15-3.47 (peaks overlapping with H₂O signal), 3.55-3.68 (m, 2H), 3.73 (s, 3H), 3.94-3.97 (m, 1H), 4.23-4.35 (m, 2H), 7.17 (d, 1H), 7.82 (s, 1H), 12.11 (s, 1H) Intermediate 126 and methyl 2-bromo- 1,3-thiazole-5- carboxylate 121 Cis(±)-Methyl 2-[4-{[(3,4- MS (ES) MH⁺: 505 for Intermediate 125 dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₆Cl₂N₄O₅S and methyl 2- yl)carbonyl]amino}-3-(2- bromo-1,3-thiazole- methoxypropoxy)piperidin-1- 5-carboxylate yl]-1,3-thiazole-5-carboxylate 122 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 511 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₂₂H₂₄Cl₂N₄O₄S; NMR: 2-bromo-1,3- yl)carbonyl]amino}-3- 1.36 (t, 3H), 1.79 (m, 2H), benzothiazole-7- methoxypiperidin-1-yl)-1,3- 2.18 (s, 3H), 3.32-3.59 (m, carboxylate (U.S. Pat. benzothiazole-7-carboxylate 4H), 4.21 (m, 1H), 4.37 (m, No. 5770758) 1H), 4.37 (q, 2H), 7.19 (d, 1H), 7.41 (t, 1H), 7.66 (m, 2H), 12.17 (s, 1H) 123 ethyl 2-((3R,4S)-4-{[(3,4- MS (ES) MH⁺: 511 for Intermediate 52 and dichloro-5-methyl-1H-pyrrol-2- C₂₂H₂₄Cl₂N₄O₄S; NMR: 2-bromo-1,3- yl)carbonyl]amino}-3- 1.36 (t, 3H), 1.79 (m, 2H), benzothiazole-7- methoxypiperidin-1-yl)-1,3- 2.18 (s, 3H), 3.32-3.59 (m, carboxylate (U.S. Pat. benzothiazole-7-carboxylate 4H), 4.21 (m, 1H), 4.37 (m, No. 5770758) 1H), 4.37 (q, 2H), 7.19 (d, 1H), 7.41 (t, 1H), 7.66 (m, 2H), 12.17 (s, 1H) 124 Cis (±)ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 448 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₁₇H₁₉Cl₂FN₄O₃S ethyl 2-bromo-1,3- yl)carbonyl]amino}-3- thiazole-4- fluoropiperidin-1-yl)-1,3- carboxylate thiazole-4-carboxylate 125 ethyl 2-((3S,4R)-4-{[(4-chloro- MS (ES) MH⁺: 475 for Intermediate 129 5-methyl-1H-pyrrol-2- C₂₂H₂₄ClN₄O₄S and 2-bromo-1,3- yl)carbonyl]amino}-3- benzothiazole-7- methoxypiperidin-1-yl)-1,3- carboxylate (U.S. Pat. benzothiazole-7-carboxylate No. 5770758)

126 Cis(±)methyl 2-(4-{[(4-chloro- MS (ES) MH⁺: 427 for Intermediate 130 3,5-dimethyl-1H-pyrrol-2- C₁₈H₂₃ClN₄O₄S and methyl 2- yl)carbonyl]amino}-3- bromo-1,3-thiazole- methoxypiperidin-1-yl)-1,3- 5-carboxylate thiazole-5-carboxylate 127 Cis(±)ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 513 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₃Cl₂N₅O₄S Intermediate 204 yl)carbonyl]amino}-3- methoxypiperidin-1- yl)[1,3]thiazolo[4,5-b]pyridine- 7-carboxylate 128 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 448 for Intermediate 31 and dichloro-5-methyl-1H-pyrrol-2- C₁₇H₁₉Cl₂FN₄O₃S ethyl 2-bromo-1,3- yl)carbonyl]amino}-3- thiazole-4- fluoropiperidin-1-yl)-1,3- carboxylate thiazole-4-carboxylate 129 ethyl 2-((3S,4R)-4-{[(4-chloro- MS (ES) MH⁺: 448 for Intermediate 130 3,5-dimethyl-1H-pyrrol-2- C₁₈H₂₂ClFN₄O₃S and ethyl 2-bromo- yl)carbonyl]amino}-3- 1,3-thiazole-4- fluoropiperidin-1-yl)-1,3- carboxylate thiazole-4-carboxylate 130 ethyl 2-((3R,4S)-4-{[(3,4- MS (ES) MH⁺: 448 for Intermediate 33 and dichloro-5-methyl-1H-pyrrol-2- C₁₇H₁₉Cl₂FN₄O₃S ethyl 2-bromo-1,3- yl)carbonyl]amino}-3- thiazole-4- fluoropiperidin-1-yl)-1,3- carboxylate thiazole-4-carboxylate

131 Cis(±)methyl 2-(3-chloro-4- MS (ES) MH⁺: 451 for Intermediate 131 {[(3,4-dichloro-5-methyl-1H- C₁₆H₁₇Cl₃N₄O₃S; NMR: and 2-bromo-1,3- pyrrol-2- 1.17 (t, 3H), 1.84 (m, 1H), thiazole-5- yl)carbonyl]amino}piperidin-1- 1.93 (m, 1H), 2.20 (s, 3H), carboxylate yl)-1,3-thiazole-5-carboxylate 3.45 (m, 1H), 3.75 (s, 3H), 3.82 (d, 1H), 4.02 (m, 1H), 4.26 (m, 1H), 4.50 (m, 1H), 4.76 (s, 1H), 7.15 (d, 1H), 7.85 (s, 1H), 12.12 (s, 1H) 132 methyl 2-{(3S,4R)-4-[({4- MS (ES) MH⁺: 456 for Intermediate 132 chloro-3-[(E)- C₁₈H₂₁ClFN₅O₄S; and methyl-2- (methoxyimino)methyl]-5- bromo-1,3-thiazole- methyl-1H-pyrrol-2- 5-carboxylate yl}carbonyl)amino]-3- fluoropiperidin-1-yl}-1,3- thiazole-5-carboxylate 133 Cis(±)-ethyl 2-(3-chloro-4- MS (ES) MH⁺: 515 for Intermediate 131 {[(3,4-dichloro-5-methyl-1H- C₂₁H₂₁Cl₃N₄O₃S and 2-bromo-1,3- pyrrol-2- benzothiazole-7- yl)carbonyl]amino}piperidin-1- carboxylate (U.S. Pat. yl)-1,3-benzothiazole-7- No. 5770758) carboxylate 134 Cis(±)-ethyl 2-(3-chloro-4- MS (ES) MH⁺: 495 for Intermediate 131 {[(3,4-dichloro-5-methyl-1H- C₁₈H₂₁Cl₃N₄O₄S and Intermediate pyrrol-2- 215 yl)carbonyl]amino}piperidin-1- yl)-4-(hydroxymethyl)-1,3- thiazole-5-carboxylate 135 Cis(±)-methyl 2-(3-chloro-4- MS (ES) MH⁺: 417 for Intermediate 133 {[(4-chloro-5-methyl-1H- C₁₆H₁₈Cl₂N₄O₃S and methyl 2- pyrrol-2-yl)carbonyl]amino}piperidin-1- bromo-1,3-thiazole- yl)-1,3-thiazole-5-carboxylate 5-carboxylate

136 Cis(±)-methyl 2-(3-chloro-4- MS (ES) MH⁺: 495 for Intermediate 131 {[(3,4-dichloro-5-methyl-1H- C₁₈H₂₁Cl₃N₄O₄S and Intermediate 17 pyrrol-2- yl)carbonyl]amino}piperidin-1- yl)-4-(methoxymethyl)-1,3- thiazole-5-carboxylate 137 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 500 for Intermediate 226 dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₃Cl₂N₅O₆; NMR: 1.3 and Intermediate 50 yl)carbonyl]amino}-3- (t, 3H), 1.65 (m, 1H), 1.8 methoxypiperidin-1-yl)-5- (m, 1H), 2.2 (s, 3H), 3.2-3.3 nitroisonicotinate (m 6H), 3.6 (m 1H), 4.3 (m, 3H), 7.1 (m, 2H), 8.9 (s, 1H), 12.1 (s, 1H) 138 Cis(±)-methyl 2-(4-{[(3,4- MS (ES) MH⁺: 431 for methyl 2-bromo- dichloro-5-methyl-1H-pyrrol-2- C₁₇H₂₀Cl₂N₄O₃S; NMR: 0.9 1,3-thiazole-5- yl)carbonyl]amino}-3- (d, 3H), 1.8 (m, 2H), 2.2 (m, carboxylate and methylpiperidin-1-yl)-1,3- 4H), 3.2 (m 3H), 3.4-3.7 (m, Intermediate 134 thiazole-5-carboxylate 3H), 3.7 (s, 3H), 4.1 (m, 1H), 4.25 (m, 1H), 7.1 (d, 1H), 7.9 (s, 1H), 12.0 (s, 1H) 139 Cis(±)-methyl 2-(4-{[(3,4- MS (ES) MH⁺: 431 for methyl 2-bromo- dichloro-5-methyl-1H-pyrrol-2- C₁₇H₂₀Cl₂N₄O₃S; NMR: 1.3 1,3-thiazole-5- yl)carbonyl]amino}-2- (d, 1H), 1.8-2.1 (m, 4H), 2.2 carboxylate and methylpiperidin-1-yl)-1,3- (s, 3H), 3.5 (m, 1H), 3.7 (m, Intermediate 135 thiazole-5-carboxylate 4H), 4.1 (m, 2H), 7.3 (s, 1H), 7.9 (s, 1H), 12.0 (s, 1H) 140 Cis(±)-isopropyl 2-(4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-6- methylisonicotinate

MS (ES) MH⁺: 483 for C₂₂H₂₈Cl₂N₄O₄; NMR: 0.9 (m, 1H), 1.3 (d, 6H), 1.7, (m, 1H), 2.2 (s, 3H), 2.4 (s, 3H), 3.1 (m, 2H), 3.5 (m, 1H), 4.2 (m, 2H), 4.7 (d, 1H), 5.1 (m, 1H), 6.8 (s, 1H), 7.0 (s, 1H), 7.15 (s, 1H), 12.1 (s, 1H) Intermediate 227 and Intermediate 50 141 Cis(±)-isopropyl 5-chloro-4-(4- MS (ES) MH⁺: 503 for Intermediate 226 {[(3,4-dichloro-5-methyl-1H- C₂₁H₂₅Cl₃N₄O₄ and Intermediate 50 pyrrol-2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)pyridine- 2-carboxylate 142 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 479 for Intermediate 215 dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₁Cl₂FN₄O₄S; NMR: and Intermediate 36 yl)carbonyl]amino}-3- 1.2 (t, 3H), 1.9 (m, 2H), 2.2 fluoropiperidin-1-yl)-4- (s, 3H), 3.6 (dd, 1H), 4.0-4.2 (hydroxymethyl)-1,3-thiazole-5- (m, 1H), 4.2 (q, 2H), 4.25- carboxylate 4.45 (m, 1H), 4.6 (s, 2H), 4.9 (m, 1H), 5.05 (m, 1H), 7.2 (d, 1H), 12.1 (s, 1H) 143 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 491 for Intermediate 215 dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₄Cl₂N₄O₅S; NMR: 1.2 and Intermediate 50 yl)carbonyl]amino}-3- (t, 3H), 1.7 (m, 2H), 2.2 (s, methoxypiperidin-1-yl)-4- 3H), 3.4 (s, 3H), 3.55 (m, (hydroxymethyl)-1,3-thiazole-5- 1H), 4.0 (m, 1H), 4.1-4.4 (m, carboxylate 4H), 4.6 (s, 2H), 7.1 (d, 1H), 12.1 (s, 1H) 144 Cis(±)-ethyl 2-(4-{[(4-chloro-3- MS (ES) MH⁺: 438 for Intermediate 136 cyano-5-methyl-1H-pyrrol-2- C₁₈H₂₀ClN₅O₄S; NMR: 1.6- and methyl 2- yl)carbonyl]amino}-3- 1.9 (m, 2H), 2.2 (s, 3H), 3.3 bromo-1,3-thiazole- methoxypiperidin-1-yl)-1,3- (s, 3H), 3.6 (m, 1H), 3.7 (s, 5-carboxylate thiazole-5-carboxylate 3H), 3.9 (m, 1H), 4.3 (m, 3H), 7.75 (d, 1H), 12.7 (s, 1H) 145 Cis(±)-ethyl 2-(4-{[(4-chloro-3- cyano-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- benzothiazole-7-carboxylate

MS (ES) MH⁺: 502 for C₂₃H₂₄ClN₅O₄S; NMR: 1.35 (t, 3H), 1.6-2.0 (m, 2H), 2.2 (s, 3H), 3.3 (s, 3H), 3.4 (m, 1H), 3.6 (s, 3H), 4.1 (m, 1H), 4.3 (m, 1H), 4.4 (q, 2H), 7.7 (m, 2H), 7.8 (m, 1H), 7.9 (t, 1H), 12.7 (s, 1H) Intermediate 136 and ethyl 2-bromo- 1,3-benzothiazole- 7-carboxylate (U.S. Pat. No. 5770758) 146 Cis(±)-ethyl 2-(4-{[(4-chloro-3- MS (ES) MH⁺: 460 for Intermediate 136 cyano-5-methyl-1H-pyrrol-2- C₂₂H₂₆ClN₅O₄ NMR: 1.3 (d, and Intermediate yl)carbonyl]amino}-3- 6H), 1.7 (m, 2H), 2.2 (s, 230 methoxypiperidin-1-yl)-1,3- 3H), 3.1 (s, 2H), 3.3 (s, 3H), thiazole-5-carboxylate 3.5 (s, 3H), 4.2 (m, 1H), 4.6 (d, 1H), 5.1 (m, 1H), 7.0 (s, 1H), 7.2 (s, 1H), 7.7 (d, 1H), 8.2 (d, 1H), 12.7 (s, 1H) 147 methyl 2-((3S,4R)-4-{[(4- MS (ES) MH⁺: 426 for Intermediate 137 chloro-3-cyano-5-methyl-1H- C₁₇H₁₇ClFN₅O₃S; NMR: 1.9 and methyl 2- pyrrol-2-yl)carbonyl]amino}-3- (m, 2H), 2.2 (s, 3H), 3.3 (s, bromo-1,3-thiazole- fluoropiperidin-1-yl)-1,3- 3H), 3.5 (dd, 1H), 3.75 (s, 5-carboxylate thiazole-5-carboxylate 3H), 4.0 (m, 1H), 4.2-4.5 (m, 2H), 5.0 (d, 1H), 7.9 (s, 1H), 8.15 (m, 1H), 12.6 (s, 1H) 148 ethyl 2-((3S,4R)-4-{[(4-chloro- MS (ES) MH⁺: 490 for Intermediate 137 3-cyano-5-methyl-1H-pyrrol-2- C₂₂H₂₁ClFN₅O₃S; NMR: and ethyl 2-bromo- yl)carbonyl]amino}-3- 1.35 (t, 3H), 1.6-2.0 (m, 2H), 1,3-benzothiazole- fluoropiperidin-1-yl)-1,3- 2.2 (s, 3H), 3.3 (m), 3.4 (m, 7-carboxylate (U.S. benzothiazole-7-carboxylate 1H), 3.6 (s, 3H), 4.1 (m, Pat. No. 5770758) 1H), 4.3 (m, 1H), 4.4 (q, 2H), 7.7 (m, 2H), 7.8 (m, 1H), 7.9 (t, 1H), 12.7 (s, 1H) 149 isopropyl 2-((3S,4R)-4-{[(4- MS (ES) MH⁺: 460 for Intermediated 137 chloro-3-cyano-5-methyl-1H- C₂₁H₂₃ClFN₅O₃ NMR: 1.3 and Intermediate pyrrol-2-yl)carbonyl]amino}-3- (d, 6H), 1.8 (m, 2H), 2.2 (s, 230 fluoropiperidin-1- 3H), 3.0 (m, 2H), 3.3 (m), yl)isonicotinate 4.1-4.2 (m, 1H), 4.45 (d, 1H), 4.9 (d, 1H), 5.0 (m, 1H), 5.1 (m, 1H), 7.0 (d, 1H), 7.3 (s, 1H), 8.1 (d, 1H), 8.3 (d, 1H), 12.6 (s, 1H) 150 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 579 for Intermediate 231 dichloro-5-methyl-1H-pyrrol-2- C₂₃H₂₉Cl₂N₅O₆S; NMR: 1.2 and Intermediate 50 yl)carbonyl]amino}-3- (m, 3H), 1.75 (m, 2H), 2.2 methoxypiperidin-1-yl)-5- (s, 3H), 3.3 (s, 3H), 3.4 (m, (morpholin-4-ylcarbonyl)-1,3- 1H), 3.5-3.6 (m, 4H), 3.8 (m, thiazole-4-carboxylate 1H), 4.2 (m, 4H), 7.15 (d,

1H), 12.1 (s, 1H) 151 Cis(±)-isopropyl 6-cyano-4-(4- MS (ES) MH⁺: 494 for Intermediate 231 {[(3,4-dichloro-5-methyl-1H- C₂₂H₂₅Cl₂N₅O₄; NMR: 1.3 and Intermediate 50. pyrrol-2-yl)carbonyl]amino}-3- (s, 6H), 1.8 (m, 2H), 2.25 (s, methoxypiperidin-1-yl)pyridine- 3H), 3.4 (s, 3H), 3.6 (m, 2-carboxylate 1H), 4.1 (d, 1H), 4.3 (m, 1H), 4.5 (d, 1H), 5.2 (m, 1H), 7.2 (d, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 12.2 (s, 1H) 152 Cis(±)-2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 475 for 2-chloro-1,3- methyl-1H-pyrrol-2- C₁₇H₂₀Cl₂N₆O₄S; NMR: 1.7 thiazole-4,5- yl)carbonyl]amino}-3- (m, 2H), 2.2 (s, 3H), 3.3 (s, dicarboxamide methoxypiperidin-1-yl)-1,3- 3H), 3.5 (m, 1H), 4.0 (m, (Robba, M.; Le thiazole-4,5-dicarboxamide 1H), 4.2 (m, 1H), 4.4 (m, Guen, Y. Bulletin 1H), 7.1 (d, 1H), 7.6 (s, 1H), de la Societe 8.1 (s, 1H), 8.2 (s, 1H), 10.4 Chimique de France (s, 1H), 12.1 (s, 1H) (1969), (6), 2152-7) and Intermediate 50. 153 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 463 for 2-chloro-1,3- methyl-1H-pyrrol-2- C₁₆H₁₇Cl₂N₆O₃S; NMR: 1.8- thiazole-4,5- yl)carbonyl]amino}-3- 1.9 (m, 2H), 2.2 (s, 3H), 3.3 dicarboxamide methoxypiperidin-1-yl)-1,3- (s, 3H), 3.4 (dd, 1H), 4.1 (m, (Robba, M.; Le thiazole-4,5-dicarboxamide 1H), 4.4 (m, 2H), 4.95 (d, Guen, Y. Bulletin 1H), 7.3 (d, 1H), 7.6 (s, 1H), de la Societe 8.1 (s, 1H), 8.2 (s, 1H), 10.4 Chimique de France (s, 1H), 12.1 (s, 1H) (1969), (6), 2152-7) and Intermediate 36. 154 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 483 for Intermediate 202 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₄Cl₂N₄O₅ and Intermediate 50 yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-5- formylisonicotinate 155 ethyl 2-((3S,4R)-4-{[(3,5- MS (ES) MH⁺: 449 for Intermediate 138 dichloro-4-methyl-1H-pyrrol-2- C₁₇H₁₉Cl₂FN₄O₃S: NMR: and ethyl 2-bromo- yl)carbonyl]amino}-3- 1.25 (m, 5H), 1.9 (s, 3H), 1,3-thiazole-5- fluoropiperidin-1-yl)-1,3- 3.6 (dd, 1H), 3.9 (m, 1H), carboxylate thiazole-5-carboxylate 4.3 (m, 2H), 5.0 (d, 1H), 7.3(d, 1H), 7.8 (s, 1H), 12.6 (s, 1H) 156 2-((3S,4R)-4-{[(3,5-dichloro-4- MS (ES) MH⁺: 465 for Intermediate 138 methyl-1H-pyrrol-2- C₁₈H₁₉Cl₂FN₄O₅S; NMR: and Intermediate yl)carbonyl]amino}-3- 1.25 (t, 3H), 1.8 (m, 2H), 1.9 252 fluoropiperidin-1-yl)-5- (s, 3H), 3.5-3.8 (m, 2H), 3.9 (ethoxycarbonyl)-1,3-thiazole- (m, 1H), 4.2 (q, 2H), 4.3 (m, 4-carboxylic acid 2H), 5.0 (d, 1H), 7.4 (d, 1H), 12.6 (s, 1H), 13.6 (s, 1H) 157 methyl 4-acetyl-2-((3S,4R)-4- MS (ES) MH⁺: 489 for Intermediate 212 {[(3,4-dichloro-5-methyl-1H- C₁₉H₂₄Cl₂N₄O₅S; NMR: and Intermediate 51 pyrrol-2-yl)carbonyl]amino}-3- 1.75 (m, 2H), 2.2 (s, 3H), methoxypiperidin-1-yl)-1,3- 2.45 (s, 3H), 3.2-3.4 (m), 3.9 thiazole-5-carboxylate (m, 1H), 4.3 (m, 2H), 7.15 (d, 1H), 12.15 (s, 1H) 158 methyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 505 for Intermediate 214 dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₆Cl₂N₄O₅S; and Intermediate 51 yl)carbonyl]amino}-3- NMR: 1.5 (s, 6H), 1.75 (m, methoxypiperidin-1-yl)-4-(1- 2H), 2.2 (s, 3H), 3.3 (s, 3H), hydroxy-1-methylethyl)-1,3- 3.55 (m, 1H), 3.8 (s, 3H), thiazole-5-carboxylate 3.8-4.0 (m, 2H), 4.2 (m, 1H), 4.5 (m, 1H), 7.15 (d, 1H), 12.2 (s, 1H) 159 methyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 503 for Intermediate 213 dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₀Cl₂N₄O₄S₂; NMR: 1.8 and Intermediate 51. yl)carbonyl]amino}-3- (m, 2H), 2.2 (s, 3H), 3.3 (m), methoxypiperidin-1- 3.6 (m, 1H), 3.95 (m, 1H), yl)thieno[2,3-d][1,3]thiazole-6- 4.3 (m, 2H), 7.2 (d, 1H), 8.0 carboxylate (s, 1H), 12.2 (s, 1H) 160 Cis(±)-methyl 2-(3- (cyclopropylmethoxy)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}piperidin- 1-yl)-1,3-thiazole-5-carboxylate

MS (ESI) M: 487 for C₂₀H₂₄Cl₂N₄O₄S; NMR 0.11 (m, 2H), 0.38 (m, 2H), 0.91 (m, 1H), 1.76 (m, 2H), 2.17 (s, 3H), 3.24-3.45 (m, 4H), 3.68 (bs, 1H), 3.73 (s, 3H), 3.94 (m, 1H), 4.25 (m, 2H), 7.14 (d, 1H), 7.82 (s, 1H), 12.16 (s, 1H) Intermediate 139 and methyl 2-bromo- 1,3-thiazole-5- carboxylate 161 Cis(±)-methyl 2-[4-{[(3,4- MS (ESI) M: 530 for Intermediate 140 and dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₁Cl₂N₅O₄S₂; NMR methyl 2-bromo- yl)carbonyl]amino}-3-(1,3- 1.66 (s, 2H), 1.91 (m, 1H), 1,3-thiazole-5- thiazol-2-ylmethoxy)piperidin- 2.10 (qd, 1H), 2.27 (s, 3H), carboxylate 1-yl]-1,3-thiazole-5-carboxylate 3.20-3.37 (m, 2H), 3.82 (s, 3H), 3.96 (m, 2H), 4.40 (m, 1H), 4.64 (d, 1H), 4.96 (dd, 2H), 7.19 (d, 1H), 7.28 (d, 1H), 9.67 (bs, 1H) 162 Cis(±)-Methyl 2-(4-{[(3,4- MS (ES) MH⁺: 461, 463 for Intermediate dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₂Cl₂N₄O₄S; ¹H-NMR: 141 and methyl-2- yl)carbonyl]amino}-3- 1.04 (t, 3H); 1.75 (m, 2H); bromo-1,3-thiazole- ethoxypiperidin-1-yl)-1,3- 2.17 (s, 3H); 3.35-3.45 (m, 5 carboxylate thiazole-5-carboxylate 3H); 3.63 (m, 2H); 3.73 (s, 3H); 3.96 (m, 1H); 4.25 (m, 2H); 7.11 (d, 1H); 7.82 (s, 1H); 12.12 (s, 1H) 163 Cis(±)-Methyl 2-(4-{[(3,4- MS (ES) MH⁺: 505, 507 for Intermediate 141 dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₆Cl₂N₄O₅S; ¹H-NMR: and Intermediate 17 yl)carbonyl]amino}-3- 1.05 (t, 3H); 1.74 (m, 2H); ethoxypiperidin-1-yl)-4- 2.17 (s, 3H); 3.27 (s, 3H); (methoxymethyl)-1,3-thiazole- 3.39-3.47 (m, 3H); 3.63 (m, 5-carboxylate 2H); 3.71 (s, 3H); 3.96 (m, 1H); 4.23 (m, 2H); 4.55 (s, 2H); 7.12 (d, 1H); 12.16 (br s, 1H) 164 Cis(±)-Ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 475, 477 for Intermediate 50 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₄Cl₂N₄O₄S; ¹H-NMR: Intermediate 236 yl)carbonyl]amino}-3- 1.22 (t, 3H); 1.72 (m, 2H); methoxypiperidin-1-yl)-4- 2.17 (s, 3H); 2.42 (s, 3H); methyl-1,3-thiazole-5- 3.31 (m, 5H); 3.52 (m, 1H); carboxylate 3.90 (m, 1H), 4.16 (q, 2H), 4.26 (m, 2H); 7.14 (d, 1H); 12.14 (brs, 1H) 165 Ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-4-methyl- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 463 465 for C₁₈H₂₁Cl₂FN₄O₃S; NMR: 1.23 (t, 3H); 1.85 (m, 2H); 2.18 (s, 3H); 2.43 (s, 3H); 3.35 (m, 1H overlapping water) 3.53 (dd, 1H); 4.00 (m, 1H); 4.16 (q, 2H); 4.30 (m, 2H); 4.94 (d, 1H); 7.24 (d, 1H); 12.09 (s, 1H) Intermediate 36 and Intermediate 236 166 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 475, 477 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₄Cl₂N₄O₄S; NMR: Intermediate yl)carbonyl]amino}-3- 1.22 (t, 3H); 1.72 (m, 2H); 236 methoxypiperidin-1-yl)-4- 2.17 (s, 3H); 2.42 (s, 3H); methyl-1,3-thiazole-5- 3.31 (m, 5H); 3.52 (m, 1H); carboxylate 3.90 (m, 1H); 4.16 (q, 2H); 4.26 (m, 2H); 7.14 (d, 1H); 12.14 (br s, 1H) 167 Trans(±)methyl 2-[4-{[(3,4- MS (ES) MH⁺: 530, 532 for Intermediate 142 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₅Cl₂N₅O₅S; NMR: yl)carbonyl]amino}-3- 1.89 (m, 1H), 2.14 (m, 1H), (morpholin-4- 2.17 (s, 3H), 3.73 (s, 3H), ylcarbonyl)piperidin-1-yl]-1,3- 3.23-3.79 (m, 12H), 3.93 thiazole-5-carboxylate (dd, 1H), 4.51 (m, 1H), 7.33 (d, 1H), 7.84 (s, 1H), 12.08 (s, 1H) 168 Cis(±)methyl 2-[4-{[(3,4- MS (ES) MH⁺: 530, 532 for Intermediate 143 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₅Cl₂N₅O₅S; NMR: yl)carbonyl]amino}-3- 1.79 (dq, 1H), 1.90 (m, 1H), (morpholin-4- 2.15 (s, 3H), 3.22-3.42 (m, ylcarbonyl)piperidin-1-yl]-1,3- 6H), 3.51-3.71 (m, 5H), 3.74 thiazole-5-carboxylate (s, 3H), 3.96 (m, 1H), 4.02 (m, 1H), 4.40 (m, 1H), 7.17 (d, 1H), 7.88 (s, 1H), 12.02 (s, 1H) 169 Cis(±)({4-{[(3,4-dichloro-5- MS (ES) MH⁺: 491, 493 for Intermediate 144 methyl-1H-pyrrol-2- C₁₈H₂₀Cl₂N₄O₆S; NMR: yl)carbonyl]amino}-1-[5- 1.61 (dq, 1H), 2.03 (m, 1H), (methoxycarbonyl)-1,3-thiazol- 2.17 (s, 3H), 3.25 (dd, 1H), 2-yl]piperidin-3-yl}oxy)acetic 3.35 (m, 1H), 3.63 (m, 1H), acid 3.74 (s, 3H), 3.88 (m, 1H), 4.06 (m, 1H), 4.17 (s, 2H), 4.23 (dd, 1H), 7.58 (d, 1H), 7.86 (s, 1H), 11.99 (s, 1H), 12.76 (s, 1H) 170 Cis(±)methyl 2-[4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3-(2- morpholin-4-yl-2- oxoethoxy)piperidin-1-yl]-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 560, 562 for C₂₂H₂₇Cl₂N₅O₆S; NMR: 1.59 (dq, 1H), 2.07 (m, 1H), 2.17 (s, 3H), 3.24 (dd, 1H), 3.27-3.56 (m, 8H), 3.61 (m, 1H), 3.74 (s, 3H), 3.85 (m, 1H), 4.05 (m, 1H), 4.24 (dd, 2H), 4.35 (q, 2H), 7.78 (d, 1H), 7.86 (s, 1H), 11.95 (s, 1H) Example 169 171 Methyl 2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 433, 435 for Intermediate 244 methyl-1H-pyrrol-2- C₁₆H₁₈Cl₂N₄O₄S yl)carbonyl]amino}-3- hydroxypiperidin-1-yl)-1,3- thiazole-5-carboxylate 172 Methyl 2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 504, 506 for Example 171 methyl-1H-pyrrol-2- C₁₉H₂₃Cl₂N₅O₅S yl)carbonyl]amino}-3- {[(ethylamino)carbonyl]oxy} piperidin-1-yl)-1,3-thiazole-5- carboxylate 173 Methyl 2-(3- MS (ES) MH⁺: 516, 518 for Example 171 {[(allylamino)carbonyl]oxy}-4- C₂₀H₂₃Cl₂N₅O₅S {[(3,4-dichloro-5-methyl-1H- pyrrol-2- yl)carbonyl]amino}piperidin-1- yl)-1,3-thiazole-5-carboxylate 174 ethyl 4-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 443 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₁Cl₂FN₄O₃; NMR: ethyl 4- yl)carbonyl]amino}-3- 1.31 (t, 3H) 1.81 (s, 2H) chloropyridine-2- fluoropiperidin-1-yl)pyridine-2- 2.19 (s, 3H) 2.69 (s, 1H) carboxylate (WO carboxylate 3.33 (s, 3H) 4.05 (s, 1H) 2004007657) 4.30 (q, 2H) 4.40 (s, 1H) 4.86 (d, 1H) 7.07 (dd, 2.73 Hz, 1H) 7.21 (d, 1H) 7.46 (d, 1H) 8.23 (d, 1H) 12.09 (s, 1H) 175 Cis(±)-diethyl 2-(4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-4,5-dicarboxylate

MS (ES) MH⁺: 533 for C₂₁H₂₆Cl₂N₄O₆S; NMR: 1.22 (t, 3H) 1.28 (t, 3H) 1.76 (d, 2H) 2.15-2.21 (m, 3H) 3.29-3.34 (m, 3H) 3.36 (s, 3H) 3.42 (s, 1H) 3.56 (s, 1H) 3.95 (s, 1H) 4.19 (q, 2H) 4.23-4.32 (m, 3H) 7.19 (d, 1H) 12.20 (s, 1H) Intermediate 50 and Intermediate 244 176 diethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 521 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₃Cl₂FN₄O₅S; NMR: Intermediate 247 yl)carbonyl]amino}-3- 1.22 (t, 3H) 1.28 (t, 3H) fluoropiperidin-1-yl)-1,3- 1.86 (d, 2H) 2.19 (s, 3H) thiazole-4,5-dicarboxylate 3.31 (s, 1H) 3.41 (s, 2H) 3.68-3.71 (dd, 1H) 3.99 (s, 1H) 4.20 (q, 2H) 4.29 (q, 2H) 4.89-5.05 (d, 1H) 7.27 (d, 1H) 12.09 (s, 1H) 177 Cis(±)-ethyl 4-(4-{[(4-chloro-5- MS (ES) MH⁺: 521 for Intermediate 55 and methyl-1H-pyrrol-2- C₂₀H₂₅ClN₄O₄ ethyl 4- yl)carbonyl]amino}-3- NMR: 1.31 (t, 3H) 1.62 (s, chloropyridine-2- methoxypiperidin-1-yl)pyridine- 1H) 1.79-1.95 (m, 1H) carboxylate (WO 2-carboxylate 2.10-2.19 (m, 3H) 3.07- 2004007657) 3.19 (m, 2H) 3.23 (s, 3H) 3.45-3.54 (m, 1H) 3.89 (s, 1H) 4.18 (s, 1H) 4.22 (d, 1H) 4.30 (q, 2H) 6.89 (d, 1H) 7.04 (dd, 1H) 7.44 (d, 1H) 7.67 (d, 1H) 8.20 (d, 1H) 11.63 (s, 1H) 178 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 622 for Intermediate 50 and dichloro-5-methyl-1H-pyrrol-2- C₂₈H₃₃Cl₂N₅O₅S Intermediate 55 yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-{[(1- methyl-1- phenylethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate 179 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 443 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₁Cl₂FN₄O₃ ethyl 2- yl)carbonyl]amino}-3- fluoroisonicotinate fluoropiperidin-1- (Konno, Akinori J. yl)isonicotinate Fluorine Chemistry (1998), 87(2), 137- 140) 180 methyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-4- (methoxymethyl)-1,3-thiazole- 5-carboxylate

MS (ES) MH⁺: 479 for C₁₈H₂₁Cl₂FN₄O₄S NMR: 1.86 (s, 2H) 2.19 (s, 3H) 3.25-3.31 (s, 3H) 3.53-3.67 (dd, 1H) 3.73 (s, 3H) 4.00 (s, 2H) 4.33 (s, 2H) 4.57 (s, 2H) 4.89-5.05 (d, 1H) 7.27 (d, 1H) 12.10 (s, 1H) Intermediate 32 and Intermediate 17 181 ethyl 4-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 493 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₂₃H₂₃Cl₂FN₄O₃ Intermediate 10 yl)carbonyl]amino}-3- fluoropiperidin-1-yl)quinoline- 2-carboxylate 182 ethyl 2-((3S,4R)-4-{[(4-chloro- MS (ES) MH⁺: 421 for Intermediate 55 and 5-methyl-1H-pyrrol-2- C₂₀H₂₅ClN₄O₄ ethyl 2- yl)carbonyl]amino}-3- NMR: 1.32 (t, 3H) 1.60 (d, fluoroisonicotinate methoxypiperidin-1- 1H) 1.84 (s, 1H) 2.14 (s, (Konno, Akinori J. yl)isonicotinate 1H) 3.13 (d, 2H) 3.20-3.24 Fluorine Chemistry (m, 3H) 3.49 (s, 1H) 4.20 (1998), 87(2), 137- (d, 2H) 4.33 (q, 2H) 4.56 140) (s, 1H) 6.89 (d, 1H) 6.97 (d, 1H) 7.23 (s, 1H) 7.64 (d, 1H) 8.24 (d, 1H) 11.62 (s, 1H) 183 methyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 491 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₄Cl₂N₄O₅S Intermediate 17 yl)carbonyl]amino}-3- NMR: 1.86-1.95 (m, 1H) methoxypiperidin-1-yl)-4- 1.97-2.04 (m, 1H) 2.26- (methoxymethyl)-1,3-thiazole- 2.31 (m, 3H) 3.16-3.31 (m, 5-carboxylate 2H) 3.47 (s, 3H) 3.48 (s, 2H) 3.50-3.55 (m, 1H) 3.82 (s, 3H) 4.05 (d, 1H) 4.25- 4.37 (m, 1H) 4.54 (s, 1H) 4.69-4.81 (m, 2H) 7.19- 7.27 (m, 1H) 9.54 (s, 1H) 184 methyl 2-((3R,4S)-4-{[(3,4- MS (ES) MH⁺:491 for Intermediate 52 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₄Cl₂N₄O₅S Intermediate 17 yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- (methoxymethyl)-1,3-thiazole- 5-carboxylate 185 Cis(±)-isopropyl 4-(4-{[(3,4- MS (ES) MH⁺: 582 for Intermediate 50 and dichloro-5-methyl-1H-pyrrol-2- C₂₆H₃₃Cl₂N₅O₆ Intermediate 249 yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-6-(morpholin-4- ylcarbonyl)pyridine-2-carboxylate

186 isopropyl 4-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 570 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₂₅H₃₀Cl₂FN₅O₅ Intermediate 249 yl)carbonyl]amino}-3- NMR: 1.32 (d, 6H) 1.78- fluoropiperidin-1-yl)-6- 1.93 (m, 2H) 2.19 (s, 3H) (morpholin-4- 3.27-3.33 (m, 4H) 3.39 (d, ylcarbonyl)pyridine-2- 2H) 3.53-3.60 (m, 2H) carboxylate 3.65 (d, 4H) 4.12 (s, 1H) 4.39 (s, 1H) 5.07-5.19 (m, 1H) 7.16-7.26 (m, 2H) 7.47 (d, 1H) 12.08 (s, 1H) 187 isopropyl 4-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 528 for Intermediate 32 and dichloro-5-methyl-1H-pyrrol-2- C₂₃H₂₈Cl₂FN₅O₄ Intermediate 250 yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-6- [(dimethylamino)carbonyl] pyridine-2-carboxylate 188 Cis(±)-2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 505 for Intermediate 50 and methyl-1H-pyrrol-2- C₁₉H₂₂Cl₂N₄O₆S Intermediate 252 yl)carbonyl]amino}-3- NMR: 1.24 (t, 3H) 1.74 (s, methoxypiperidin-1-yl)-5- 2H) 2.18 (s, 3H) 3.36 (s, (ethoxycarbonyl)-1,3-thiazole- 4H) 3.56 (s, 1H) 3.93 (s, 1H) 4-carboxylic acid 4.19 (s, 3H) 4.29 (s, 2H) 7.13 (s, 1H) 12.11 (s, 1H) 13.51 (s, 1H) 189 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 493 for Intermediate 32 and methyl-1H-pyrrol-2- C₁₈H₁₉Cl₂FN₄O₅S Intermediate 252 yl)carbonyl]amino}-3- NMR: 1.19-1.27 (m, 3H) fluoropiperidin-1-yl)-5- 1.85 (d, 2H) 2.18 (s, 3H) (ethoxycarbonyl)-1,3-thiazole- 3.26-3.35 (m, 1H) 3.53 (d, 4-carboxylic acid 1H) 3.98 (s, 2H) 4.18 (q, 1H) 4.31 (s, 2H) 4.88-5.04 (s, 1H) 7.26 (d, 1H) 12.08 (s, 1H) 13.55 (s, 1H) 190 2-((3R,4S)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-5- (ethoxycarbonyl)-1,3-thiazole- 4-carboxylic acid

MS (ES) MH⁺: 505 for C₁₉H₂₂Cl₂N₄O₆S NMR: 1.16 (t, 3H) 1.69 (s, 2H) 2.12 (s, 2H) 3.30 (s, 3H) 3.50 (s, 2H) 3.89 (s, 2H) 4.13 (q, 2H) 4.17-4.29 (m, 2H) 7.10 (d, 1H) 12.10 (s, 1H) 13.50 (s, 1H) Intermediate 52 and Intermediate 252 191 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 505 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₁₉H₂₂Cl₂N₄O₆S Intermediate 252 yl)carbonyl]amino}-3- NMR: 1.22 (t, 3H) 1.75 (s, methoxypiperidin-1-yl)-4- 2H) 2.18 (s, 3H) 3.31 (d, carboxy-1,3-thiazole-5- 1H) 3.36 (s, 3H) 3.42 (s, 1H) carboxylate 3.56 (s, 1H) 3.95 (s, 1H) 4.14-4.22 (m, 2H) 4.29 (s, 1H) 7.16 (d, 1H) 12.16 (s, 2H) 13.56 (s, 1H) 192 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 461 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₂Cl₂N₄O₄S ethyl 2-bromo-1,3- yl)carbonyl]amino}-3- thiazole-4- methoxypiperidin-1-yl)-1,3- carboxylate thiazole-4-carboxylate 193 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 455 for Intermediate 51 and dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₄Cl₂N₄O₄ ethyl 2- yl)carbonyl]amino}-3- NMR: 1.32 (s, 3H) 1.84 (s, fluoroisonicotinate methoxypiperidin-1- 2H) 2.22 (s, 3H) 3.36 (s, (Konno, Akinori J. yl)isonicotinate 3H) 3.45 (s, 1H) 4.16 (s, 1H) Fluorine Chemistry 4.25 (s, 1H) 4.31 (s, 2H) (1998), 87(2), 137- 4.81 (s, 1H) 7.04 (s, 1H) 140) 7.26 (s, 1H) 8.21 (s, 1H) 10.53 (s, 1H)

Example 194 Cis(±)-ethyl 5-amino-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate

A solution of SnCl₂ dihydrate (870 mg, 3.8 mmol) in 5 ml concentrated HCl was added to a solution of 436 mg (0.87 mmol) of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-nitroisonicotinate (Example 308) in 30 ml acetic acid. The mixture was stirred at room temperature overnight. Solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying (MgSO₄), removal of solvent and chromatography on silica gel (100% CH₂Cl₂ followed by gradient elution to 100% EtOAc and then to 10% MeOH in EtOAc) gave 230 mg of product. MS (ES)(MH⁺): 470 for C₂₀H₂₅Cl₂N₅O₄; NMR (CDCl₃): 1.5 (t, 3H), 2.1 (m, 2H) 2.4 (s, 3H), 3.2 (m, 2H), 3.6 (s, 3H), 3.65 (m, 1H), 4.0 (m, 1H), 4.4 (m, 1H), 4.5 (q, 2H), 7.3 (s, 1H), 8.0 (s, 1H), 9.5 (s, 1H).

Example 195 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-[(methoxycarbonyl)amino]isonicotinate

Methylchlorofomate (15 μl, 0.19 mmol) was added to a solution of 60 mg (0.13 mmol) of Cis(±)-ethyl 5-amino-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 194) in 3 ml pyridine. After stirring at room temperature overnight, 7 μl more methylchloroformate was added. Solvent was removed and the residue was partitioned between EtOAc and NaHCO₃ (aqueous). The EtOAc was separated and washed with water and brine. Drying (MgSO₄) and removal of solvent gave 43 mg of product. NMR (d₆-DMSO): 1.3 (t, 3H), 1.7 (m, 2H) 2.2 (s, 3H), 3.1 (m, 2H), 3.3 (s, 3H), 3.5 (m, 1H), 3.6 (s, 3H), 4.0-4.3 (m, 4H), 4.6 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 8.2 (s, 1H), 9.1 (s, 1H), 12.2 (s, 1H).

Example 196 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-[(methylsulfonyl)amino]isonicotinate

Methanesulfonyl chloride (16 μl, 21 mmol) was added to 66 mg (0.14 mmol) of Cis(±)-ethyl 5-amino-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 194) in 3 ml pyridine. After stirring for 1 h, 5 μl more methanesulfonyl chloride was added. Stirred at room temperature overnight. Solvent was removed, and the residue was partitioned between EtOAc and Na₂CO₃ (aqueous). The EtOAc was separated and washed with water and brine. Drying (MgSO₄) and removal of solvent gave 63 mg of product. MS (ES)(MH⁺): 534 for C₂₁H₂₇Cl₂N₅O₆S, NMR (d₆-DMSO): 1.4 (t, 3H), 1.8 (m, 2H) 2.2 (s, 3H), 2.9 (s, 3H), 3.1-3.2 (m, 2H), 3.3-3.5 (m), 3.6 (m, 1H), 4.2-4.3 (m, 2H), 4.4 (q, 2H), 4.7 (m, 1H), 7.1 (s, 1H), 7.2 (d, 1H), 8.2 (s, 1H), 12.2 (s, 1H).

Example 197 Cis(±)-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(ethoxycarbonyl)nicotinic acid

A solution of 133 mg (0.84 mmol) KMnO₄ in 5 ml water was added to a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-formylisonicotinate (Example 154) in 20 ml acetone, and the mixture was stirred at room temperature for 4 h. After quenching with aqueous NaHSO₃, the mixture was acidified to about pH=4 with 1N HCl and extracted twice with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO₄) and concentrated to give a solid that was triturated with MeOH to give 175 mg of product. MS (ES) MH⁺: 499 for C₂₁H₂₄Cl₂N₄O₆; NMR: 1.25 (t, 3H), 1.5-1.8, (m, 3H), 2.1 (s, 3H), 3.1 (m, 3H), 3.3 (s, 3H), 3.5 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 4.9 (m, 1H), 6.9 (s, 1H), 7.1 (d, 1H), 8.6 (s, 1H), 12.1 (s, 1H), 13.3 (s, 1H).

Example 198 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-{[(1-methyl-1-phenylethyl)amino]carbonyl}isonicotinate

HATU (87 mg, 24 mmol) was added to a solution of 118 mg (0.24 mmol) Cis(±)-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(ethoxycarbonyl)nicotinic acid (Example 197), 0.040 ml (28 mmol) Et₃N and 33 mg (0.24 mmol) cumylamine in 3 ml DMF. After stirring at room temperature overnight, the mixture was diluted with water and extracted with EtOAc. The EtOAc was washed 2 times with water and once with brine before being dried (MgSO₄) and concentrated to give 103 mg of a solid. MS (ES) MH⁺: 616 for C₃₀H₃₅Cl₂N₅O₅.

Examples 199-200

The following Examples were prepared by the procedure described in Example 198 from the starting materials (SM) indicated.

Ex Compound Data SM 199 ethyl 2-((3S,4R)-4-{[(3,5- MS (ES) MH⁺: 610 for Example 156 and dichloro-4-methyl-1H-pyrrol- C₂₇H₃₀Cl₂FN₅O₄S; cumylamine 2-yl)carbonyl]amino}-3- NMR: 1.2 (t, 3H), 1.5 (s, fluoropiperidin-1-yl)-4-{[(1- 6H), 1.65 (m, 2H), 1.9 methyl-1- (s, 3H), 3.6 (m, 1H), 4.0 phenylethyl)amino]carbonyl}- (m, 1H), 4.1-4.3 (m, 1,3-thiazole-5-carboxylate 4H), 4.3 (dd, 1H), 4.95 (d, 1H), 7.0-7.5 (m, 5H), 8.6 (s, 1H), 12.6 (s, 1H) 200 ethyl 2-((3S,4R)-4-{[(3,5- dichloro-4-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-4-{[(2- morpholin-4- ylethyl)amino]carbonyl}-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 605 for C₂₄H₃₁Cl₂FN₆O₆S; NMR: 1.2 (t, 3H), 1.8 (m, 2H), 1.9 (s, 3H), 2.3 (m, 4H), 3.6 (m, 5H), 4.0 (m, 1H), 4.2 (q, 2H), 4.3 (m, 2H), 4.95 (d, 1H), 7.35 (d, 1H), 8.4 (t, 1H), 12.6 (s, 1H) Example 156 and (2- morpholin-4- ylethyl)amine

Example 201 Cis(±)-ethyl 5-(aminocarbonyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate

A solution of 103 mg (0.17 mmol) of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-{[(1-methyl-1-phenylethyl)amino]carbonyl} isonicotinate (Example 198) in 10 ml TFA was heated at 40° C. overnight and at 50° C. for 6 h. Solvent was removed and the residue was triturated with MeOH to give 62 mg of a white solid. MS (ES) MH⁺: 498 for C₂₁H₂₅Cl₂N₅O₅.

Example 202

The following Example was prepared by the procedure described in Example 201 from the starting materials (SM) indicated.

Ex Compound Data SM 202 5-thiazolecarboxylic acid, 4- MS (ES) MH⁺: Example (aminocarbonyl)-2-[(3S,4R)-4- 492 for 199 [[(3,5-dichloro-4- C₁₈H₂₀Cl₂FN₅O₄SE methyl-1H-pyrrol-2- yl)carbonyl]amino]-3-fluoro-1- piperidinyl]-, ethyl ester

Example 203 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(dimethylamino)carbonyl]-1,3-thiazole-5-carboxylate

A solution of Cis(±)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (0.062 g, 0.12 mmol, Example 188), dimethylamine (0.06 mL, 2M solution in THF, Aldrich), HATU (0.05 g, 0.13 mmol) and triethylamine (0.018 mL, 0.13 mmol) was stirred at room temperature until complete by LCMS (about 30 min). The crude reaction mixture was slowly poured into water and the resulting white precipitate was filtered, washed with water and dried under vacuum to yield pure product (0.028 g). MS (ES) MH⁺: 532 for C₂₁H₂₇Cl₂N₅O₅S; NMR: 1.20 (t, 3 H) 1.76 (s, 2 H) 2.18 (s, 3 H) 2.78 (s, 3 H) 2.93 (s, 3 H) 3.29 (d, 1 H) 3.36 (s, 3 H) 3.39-3.43 (m, 1 H) 3.55 (s, 1 H) 3.91 (s, 1 H) 4.15 (q, 2 H) 4.29 (s, 2 H) 7.15 (d, 1 H) 12.14 (s, 1 H).

Examples 204-241

The following Examples were prepared by the procedure described in Example 203 from the starting materials (SM) indicated

Ex Compound Data SM 204 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 574 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₃H₂₉Cl₂N₅O₆S; morpholine 2-yl)carbonyl]amino}-3- NMR: 1.21 (t, 3H) 1.74 (s, 2 methoxypiperidin-1-yl)-4- H) 2.17 (s, 3H), 3.11-3.17 (morpholin-4-ylcarbonyl)- (m, 2H) 3.34 (s, 3H) 3.38 (s, 1,3-thiazole-5-carboxylate 1H) 3.47-3.59 (m, 5H) 3.62 (s, 2H) 3.87 (s, 1H) 4.17 (q, 2H) 4.29 (s, 2H) 7.13 (d, 1 H) 12.13 (s, 1H) 205 ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-4- (morpholin-4-ylcarbonyl)- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 562 for C₂₂H₂₆Cl₂FN₅O₅S; NMR: 1.16 (t, 3H) 1.80 (s, 2H) 2.12 (s, 3H) 3.09 (d, 2H) 3.45 (s, 2H) 3.50 (s, 2H) 3.57 (s, 2H) 3.92 (s, 1H) 4.12 (q, 2H) 4.26 (s, 3H) 4.82 (s, 1H) 4.99 (s, 1H) 7.19 (s, 1H) 12.02 (s, 1H) Example 189 and morpholine 206 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 534 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₀H₂₅Cl₂N₅O₆S; NMR: 1.18- methoxylamine 2-yl)carbonyl]amino}-3- 1.25 (m, 3H) 1.75 (s, 2H) hydrochloride methoxypiperidin-1-yl)-4- 2.17 (s, 3H) 3.35 (s, 3H) [(methoxyamino)carbonyl]- 3.54 (s, 2H) 3.67 (s, 3H) 1,3-thiazole-5-carboxylate 3.95 (s, 2H) 4.14-4.22 (m, 2 H), 4.28 (s, 2H) 7.13 (d, 1H) 11.48 (s, 1H) 12.13 (s, 1H) 207 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 522 for Example 189 and dichloro-5-methyl-1H-pyrrol- C₁₉H₂₂cL₂FN₅O₅S; NMR: methoxylamine 2-yl)carbonyl]amino}-3- 1.16 (t, 3H) 1.79 (s, 2H) hydrochloride fluoropiperidin-1-yl)-4- 2.12 (s, 3H) 3.29 (s, 2H) [(methoxyamino)carbonyl]- 3.62 (s, 3H) 3.94 (s, 1H) 1,3-thiazole-5-carboxylate 4.12 (q, 2H) 4.25 (s, 2H) 4.82-4.98 (s, 1H) 7.18 (d, 1 H) 11.44 (s, 1H) 12.03 (s, 1 H) 208 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 572 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₄H₃₁Cl₂N₅O₅S; NMR: 1.22 piperidine 2-yl)carbonyl]amino}-3- (s, 3H) 1.43 (s, 2H) 1.56 (s, methoxypiperidin-1-yl)-4- 4H) 1.74 (s, 2H) 2.17 (s, 3 (piperidin-1-ylcarbonyl)-1,3- H) 3.12 (s, 2H) 3.36 (s, 3H) thiazole-5-carboxylate 3.52 (s, 3H) 4.16 (s, 2H) 4.27 (s, 2H) 7.15 (s, 1H) 12.18 (s, 1H) 209 ethyl 2-((3R,4S)-4-{[(3,4- MS (ES) MH⁺: 622 for Example 190 and dichloro-5-methyl-1H-pyrrol C₂₈H₃₃Cl₂N₅O₅S; NMR: 1.18 cumylamine 2-yl)carbonyl]amino}-3- (t, 3H) 1.53 (s, 3H) 1.56 (s, 3 methoxypiperidin-1-yl)-4- H) 1.71 (s, 2H) 2.13 (s, 3H) {[(1-methyl-1- 3.34 (s, 3H) 3.51 (s, 2H) phenylethyl)amino]carbonyl}- 3.92 (s, 2H) 4.15 (q, 2H) 1,3-thiazole-5-carboxylate 4.26 (s, 2H) 7.12 (dd, 2H) 7.23 (t, 2H) 7.40 (d, 2H) 8.56 (s, 1H) 12.11 (s, 1H) 210 ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-4-{[(1- methyl-1- phenylethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 610 for C₂₇H₃₀Cl₂FN₅O₄S; NMR: 1.23 (t, 3H) 1.61 (s, 6H) 1.86 (s, 2H) 2.19 (s, 3H) 3.31 (s, 3H) 3.55 (s, 1H) 4.04 (s, 1H) 4.22 (q, 1H) 4.32 (s, 2H) 4.90-5.06 (d, 1H) 7.20 (d, 1H) 7.31 (t, 3H) 7.47 (d, 2H) 8.63 (s, 1H) 12.12 (s, 1H) Example 189 and cumylamine 211 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 506 for Example 189 and dichloro-5-methyl-1H-pyrrol- C₁₉H₂₂Cl₂FN₅O₄S; NMR: methylamine 2-yl)carbonyl]amino}-3- 1.14 (t, 3H) 1.77 (s, 2H) fluoropiperidin-1-yl)-4- 2.12 (s, 3H) 2.62 (d, 3H) 3.33 [(methylamino)carbonyl]-1,3- (s, 1H) 3.43-3.63 (s, 1H) thiazole-5-carboxylate 3.94 (s, 1H) 4.09 (q, 2H) 4.23 (s, 2H) 4.82-4.98 (s, 1 H) 7.20 (d, 1H) 8.27 (d, 1H) 12.03-12.12 (m, 1H) 212 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 548 for Example 188 and 2- dichloro-5-methyl-1H-pyrrol- C₂₁H₂₇Cl₂N₅O₆S aminoethanol 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- {[(2- hydroxyethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate 213 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 622 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₈H₃₃Cl₂N₅O₅S; cumylamine 2-yl)carbonyl]amino}-3- NMR: 1.23 (t, 3H) 1.59 (s, 3 methoxypiperidin-1-yl)-4- H) 1.62 (s, 3H) 1.77 (s, 2H) {[(1-methyl-1- 2.19 (s, 3H) 3.31 (s, 1H) phenylethyl)amino]carbonyl}- 3.36 (s, 1H) 3.40 (s, 3H) 1,3-thiazole-5-carboxylate 3.57 (s, 1H) 3.96 (s, 1H) 4.21 (q, 2H) 4.32 (s, 2H) 7.12-7.22 (m, 2H) 7.29 (t, 2 H) 7.46 (d, 2H) 8.62 (s, 1H) 214 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 518 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₀H₂₅Cl₂N₅O₅S; methylamine 2-yl)carbonyl]amino}-3- NMR: 1.20 (s, 3H) 1.74 (s, 2 methoxypiperidin-1-yl)-4- H) 2.17 (s, 3H) 2.68 (s, 3H) [(methylamino)carbonyl]-1,3- 3.30 (s, 2H) 3.36 (s, 3H) thiazole-5-carboxylate 3.55 (s, 1H) 3.99 (s, 1H) 4.15 (s, 2H) 4.26 (s, 2H) 7.14 (s, 1H) 8.32 (s, 1H) 12.18 (s, 1H) 215 Cis(±)-ethyl 2-(4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- {[(2- methoxyethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 562 for C₂₂H₂₉Cl₂N₅O₆S; NMR: 1.15-1.25 (m, 3H) 1.74 (s, 2H) 2.18 (s, 3H) 3.26 (s, 3H) 3.30 (s, 1H) 3.36 (s, 3H) 3.41 (d, 3H) 3.55 (s, 1H) 4.00 (s, 1H) 4.10-4.19 (m, 2H) 4.26 (s, 2+nlH) 7.15 (d, 1H) 8.44-8.56 (m, 1H) 12.16 (s, 1H) Example 188 and (2-methoxyethyl)amine 216 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 562 for Example 188 and 2- dichloro-5-methyl-1H-pyrrol- C₂₂H₂₉Cl₂N₅O₆S; aminopropan-1-ol 2-yl)carbonyl]amino}-3- NMR: 1.08 (d, 2H) 1.22 (t, 3 methoxypiperidin-1-yl)-4- H) 1.75 (s, 2H) 2.18 (s, 3H) {[(2-hydroxy-1- 3.37 (s, 3H) 3.47 (d, 1H) methylethyl)amino]carbonyl}- 3.55 (s, 1H) 3.81-3.92 (m, 1 1,3-thiazole-5-carboxylate H) 3.99 (s, 1H) 4.17 (q, 2H) 4.27 (s, 2H) 4.62 (s, 2H) 7.15 (d, 1H) 8.20 (d, 1H) 12.17 (s, 1H) 217 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 562 for Example 188 and 1- dichloro-5-methyl-1H-pyrrol- C₂₂H₂₉Cl₂N₅O₆S; aminopropan-2-ol 2-yl)carbonyl]amino}-3- NMR: 1.07 (d, 3H) 1.21 (t, 3 methoxypiperidin-1-yl)-4- H) 1.75 (s, 2H) 2.18 (s, 3H) {[(2- 3.03-3.18 (m, 2H) 3.36 (s, 3 hydroxypropyl)amino]carbon H) 3.41 (s, 1H) 3.55 (s, 1H) yl}-1,3-thiazole-5-carboxylate 3.74 (s, 1H) 3.98 (s, 1H) 4.11-4.19 (m, 2H) 4.19 (s, 1 H) 4.30 (s, 1H) 4.61 (s, 1H) 7.15 (d, 1H) 8.33-8.43 (m, 1 H) 12.16 (s, 1H) 218 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 518 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₀H₂₅Cl₂N₅O₅S; methylamine 2-yl)carbonyl]amino}-3- NMR: 1.21 (s, 3H) 1.74 (s, 2 hydrochloride methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 2.69 (s, 3H) [(methylamino)carbonyl]-1,3- 3.17 (s, 2H) 3.36 (s, 3H) thiazole-5-carboxylate 3.55 (s, 1H) 3.98 (s, 1H) 4.14 (s, 2H) 4.27 (s, 2H) 7.13 (s, 1H) 8.33 (s, 1H) 12.17 (s, 1H) 219 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 562 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₂H₂₉Cl₂N₅O₆S (2-methoxyethyl)amine 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- {[(2- methoxyethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate 220 ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1S)-2-hydroxy-1- methylethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 562 for C₂₂H₂₉Cl₂N₅O₆S Example 191 and (2S)-2- aminopropan-1-ol 221 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 562 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₂H₂₉Cl₂N₅O₆S [(1R)-2-methoxy-1- 2-yl)carbonyl]amino}-3- methylethyl]amine methoxypiperidin-1-yl)-4- ({[(1R)-2-hydroxy-1- methylethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate 222 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 568 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₁H₂₅Cl₂F₂N₅O₅S; difluoroethylamine 2-yl)carbonyl]amino}-3- NMR: 1.21 (t, 3H) 1.75 (s, 2 methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.36 (s, 3H) {[(2,2- 3.44 (s, 1H) 3.55 (s, 3H) difluoroethyl)amino]carbonyl}- 3.98 (s, 1H) 4.16 (q, 2H) 1,3-thiazole-5-carboxylate 4.26 (s, 2H) 5.88-6.26 (t, 1H) 7.15 (d, 1H) 8.88 (s, 1H) 12.16 (s, 1H) 223 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 571 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₂H₂₄Cl₂N₆O₆S; isoxazol-3-amine 2-yl)carbonyl]amino}-3- NMR: 1.12 (t, 3H) 1.77 (d, 2 methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.38 (s, 3H) [(isoxazol-3- 3.56 (s, 2H) 3.98 (s, 2H) ylamino)carbonyl]-1,3- 4.14 (q, 2H) 4.19-4.34 (m, 2 thiazole-5-carboxylate H) 6.99 (d, 1H) 7.16 (d, 1H) 8.86 (d, 1H) 11.59 (s, 1H) 12.17 (s, 1H) 224 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 574 for Example 188 and dichloro-5-methyl-1H-pyrrol- C₂₃H₂₉Cl₂N₅O₆S; (3R)- 2-yl)carbonyl]amino}-3- NMR: 1.21 (t, 3H) 1.75 (d, 2 tetrahydrofuran-3- methoxypiperidin-1-yl)-4- H) 1.87 (s, 1H) 2.09 (s, 1H) amine 4- {[(3R)-tetrahydrofuran-3- 2.18 (s, 3H) 3.36 (s, 3H) methylbenzensulfonate ylamino]carbonyl}-1,3- 3.42 (s, 1H) 3.55 (s, 2H) thiazole-5-carboxylate 3.69 (s, 1H) 3.78 (s, 2H) 4.01 (s, 1H) 4.17 (d, 2H) 4.28 (s, 3H) 7.15 (d, 1H) 8.67 (d, 1H) 12.17 (s, 1H) 225 Cis(±)-ethyl 2-(4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1R,2S)-2- fluorocyclopropyl]amino} carbonyl)-1,3-thiazole-5- carboxylate

MS (ES) MH⁺: 562 for C₂₂H₂₆Cl₂FN₅O₅S; NMR: 1.07 (s, 2H) 1.21 (t, 3+nlH) 1.75 (s, 2H) 2.18 (s, 3H) 2.73 (s, 1H) 3.36 (s, 3H) 3.41 (s, 1H) 3.55 (s, 1H) 3.99 (s, 1H) 4.17 (s, 2H) 4.26 (s, 3H) 4.62-4.84 (d, 1H) 7.16 (s, 1H) 8.64 (s, 1H) 12.17 (s, 1H) Example 188 and (1R,2S)-2- fluorocyclo- propanamine 4- methylbenzenesulfonate 226 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 576 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₃H₃₁Cl₂N₅O₆S; [(1S)-2-methoxy-1- 2-yl)carbonyl]amino}-3- NMR: 1.09 (d, 3H) 1.22 (t, 3 methylethyl]amine methoxypiperidin-1-yl)-4- H) 1.75 (s, 2H) 2.18 (s, 3H) ({[(1S)-2-methoxy-1- 3.17 (s, 2H) 3.26 (s, 3H) methylethyl]amino}carbonyl)- 3.37 (s, 3H) 3.55 (s, 1H) 1,3-thiazole-5-carboxylate 4.01 (d, 1H) 4.17 (d, 2H) 4.27 (s, 2H) 7.16 (s, 1H) 8.32 (d, 1H) 12.16 (s, 1H) 227 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 542 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₂H₂₅Cl₂N₅O₅S; propargylamine 2-yl)carbonyl]amino}-3- NMR: 1.22 (s, 3H) 1.74 (s, 2 methoxypiperidin-1-yl)-4- H) 2.18 9s, 3H) 3.16 (s, 1H) [(prop-2-yn-1- 3.40 (m, 5H) 3.55 (d, 1H) ylamino)carbonyl]-1,3- 3.96 (s, 3H) 4.17 (s, 2H) thiazole-5-carboxylate 4.28 (s, 2H) 7.14 (s, 1H) 8.87 (s, 1H) 12.16 (s, 1H) 228 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 576 for Example 191 and 2- dichloro-5-methyl-1H-pyrrol- C₂₃H₃₁Cl₂N₅O₆S amino-2- 2-yl)carbonyl]amino}-3- NMR: 1.26 (s, 6H) 1.75 (s, 2 methylpropan-1-ol methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.37 (s, 3H) {[(2-hydroxy-1,1- 3.44 (s, 3H) 3.56 (s, 1H) dimethylethyl)amino]carbonyl}- 4.03 (s, 1H) 4.19 (s, 2H) 1,3-thiazole-5-carboxylate 4.28 (s, 2H) 4.67 (s, 1H) 7.16 (s, 1H) 7.87 (s, 1H) 12.17 (s, 1H) 229 2-((3S,4R)-4-{[(3,4-dichloro- MS (ES) MH⁺: 562 for Example 191 and 5-methyl-1H-pyrrol-2- C₂₂H₂₆Cl₂FN₅O₅S; (1R,2S)-2- yl)carbonyl]amino}-3- NMR: 1.08 (s, 3H) 1.21 (t, 3 fluorocyclo- methoxypiperidin-1-yl)-4- H) 1.76 (s, 2H) 2.18 (s, 3H) propanamine 4- {[(2-hydroxy-1,1 3.36 (s, 3H) 3.41 (s, 1H) methylbenzenesulfonate dimethylethyl)amino]carbonyl}- 3.55 (s, 1H) 3.97 (s, 1H) 1,3-thiazole-5-carboxylic 4.09-4.19 (m, 2H) 4.27 (s, 2 acid H) 4.61-4.83 (s, 1H) 7.15 (d, 1H) 8.64 (s, 1H) 12.16 (s, 1H) 230 ethyl 4-{[(1- cyanocyclopropyl)amino] carbonyl}-2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 569 for C₂₃H₂₆Cl₂N₆O₅S; NMR: 1.21 (q, 5H) 1.50- 1.61 (m, 2H) 1.75 (s, 2H) 2.18 (s, 3H) 3.36 (s, 3H) 3.40 (s, 1H) 3.55 (s, 1H) 4.01 (s, 1H) 4.13-4.22 (m, 2 H) 4.28 (s, 2H) 7.14 (d, 1H) 9.36 (s, 1H) 12.17 (s, 1H) Example 191 and 1- aminocyclopropane carbonitrile 231 ethyl 4- MS (ES) MH⁺: 544 for Example 191 and [(cyclopropylamino)carbonyl]- C₂₂H₂₇Cl₂N₅O₅S; cyclopropylamine 2-((3S,4R)-4-{[(3,4- NMR: 0.49 (s, 2H) 0.66 (d, 2 dichloro-5-methyl-1H-pyrrol- H) 1.22 (s, 3H) 1.75 (s, 2H) 2-yl)carbonyl]amino}-3- 2.18 (s, 3H) 2.72 (s, 1H) methoxypiperidin-1-yl)-1,3- 3.38 (m, 4H) 3.55 (s, 1H) thiazole-5-carboxylate 3.99 (s, 1H) 4.17 (s, 2H) 4.27 (s, 2H) 7.16 (s, 1H) 8.44 (s, 1H) 12.17 (s, 1H) 232 ethyl 4-{[(1-cyano-1- MS (ES) MH⁺: 571 for Example 191 and 2- methylethyl)amino]carbonyl}- C₂₃H₂₈Cl₂N₆O₅S; amino-2- 2-((3S,4R)-4-{[(3,4- NMR: 1.23 (t, 3H) 1.62 (s, 6 methylpropanenitrile dichloro-5-methyl-1H-pyrrol- H) 1.76 (s, 2H) 2.18 (s, 3H) 2-yl)carbonyl]amino}-3- 3.37 (s, 3H) 3.56 (s, 1H) methoxypiperidin-1-yl)-1,3- 4.04 (s, 1H) 4.15-4.22 (m, 2 thiazole-5-carboxylate H) 4.23 (s, 2H) 7.15 (d, 1H) 9.07 (s, 1H) 12.17 (s, 1H) 233 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 606 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₃H₂₉Cl₂N₅O₈S methyl serinate 2-yl)carbonyl]amino}-3- NMR: 1.21 (t, 3H) 1.75 (s, 2 methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.37 (s, 3H) ({[1-(hydroxymethyl)-2- 3.56 (s, 1H) 3.66 (s, 2H) methoxy-2- 3.69-3.75 (m, 1H) 4.00 (s, 1 oxoethyl]amino}carbonyl)- H) 4.16 (q, 2H) 4.27 (s, 2H) 1,3-thiazole-5-carboxylate 4.42-4.54 (m, 1H) 4.98 (s, 1 H) 7.16 (d, 1H) 8.75 (dd, 1 H) 12.17 (s, 1H) 234 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 617 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₅H₃₄Cl₂N₆O₆S; (2-morpholin-4- 2-yl)carbonyl]amino}-3- NMR: 1.22 (d, 3H) 1.75 (s, 2 ylethyl)amine methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.34 (m, 5H) {[(2-morpholin-4- 3.36 (s, 3H) 3.55 (s, 1H) ylethyl)amino]carbonyl}-1,3- 3.80 (s, 2H) 3.91 (s, 2H) thiazole-5-carboxylate 4.02 (s, 1H) 4.16 (s, 2H) 4.27 (s, 2H) 4.94 (s, 1H) 7.14 (s, 1H) 8.59 (s, 1H) 12.16 (s, 1H) 235 ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- {[(1,3-dioxolan-2- ylmethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 590 for C₂₃H₂₉Cl₂N₅O₇S NMR: 1.22 (d, 3H) 1.75 (s, 2+nlH) 2.18 (s, 3H) 3.36 (s, 4H) 3.55 (s, 1H) 3.80 (s, 2H) 3.91 (s, 2H) 4.00 (s, 1H) 4.16 (s, 3H) 4.28 (s, 2H) 4.94 (s, 1H) 7.14 (s, 1H) 8.59 (s, 1H) 12.16 (s, 1H) Example 191 and (1,3-dioxolan-2- ylmethyl)amine 236 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 629 for Example 191 and 1-(3- dichloro-5-methyl-1H-pyrrol- C₂₆H₃₄Cl₂N₆O₆S aminopropyl)pyrrolidin- 2-yl)carbonyl]amino}-3- 2-one methoxypiperidin-1-yl)-4- ({[3-(2-oxopyrrolidin-1- yl)propyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate 237 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 595 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₅H₂₈Cl₂N₆O₅S; (pyridin-2- 2-yl)carbonyl]amino}-3- NMR: 1.18 (t, 3H) 1.76 (s, 2 ylmethyl)amine methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.46 (s, 2H) {[(pyridin-2- 3.57 (s, 1H) 3.99 (s, 1H) ylmethyl)amino]carbonyl}- 4.16 (q, 2H) 4.28 (s, 2H) 1,3-thiazole-5-carboxylate 4.50 (d, 2H) 7.16 (d, 1H) 7.34 (s, 1H) 7.53 (d, 1H) 7.81-7.93 (m, 1H) 8.53 (s, 1 H) 9.07 (t, 1H) 12.17 (s, 1H) 238 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 578 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₂H₂₉Cl₂N₅O₅S₂ [2-(methylthio 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[2- (methylthio)ethyl]amino} carbonyl)-1,3-thiazole-5- carboxylate 239 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 585 for Example 191 and 1- dichloro-5-methyl-1H-pyrrol- C₂₃H₂₆Cl₂N₆O₆S; (1,3-oxazol-2- 2-yl)carbonyl]amino}-3- NMR: 1.17 (t, 3H) 1.74 (s, 2 yl)methanamine methoxypiperidin-1-yl)-4- H) 2.18 (s, 3H) 3.37 (s, 3H) hydrochloride {[(1,3-oxazol-2- 3.55 (s, 1H) 4.00 (s, 1H) ylmethyl)amino]carbonyl}- 4.13 (d, 2H) 4.26 (s, 2H) 1,3-thiazole-5-carboxylate 4.49 (d, 2H) 7.11-7.25 (m, 2 H) 8.08 (s, 1H) 9.07 (s, 1H) 12.16 (s, 1H) 240 ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- {[(2- fluoroethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 550 for C₂₁H₂₆Cl₂FN₅O₅S; NMR: 1.21 (t, 3H) 1.74 (d, 2+nlH) 2.18 (s, 3H) 3.40 (s, 3H) 3.55 (s, 3H) 3.99 (s, 1H) 4.17 (d, 2H) 4.27 (s, 2H) 4.42 (s, 1H) 4.58 (s, 1H) 7.14 (s, 1H) 8.70 (s, 1H) 12.17 (s, 1H) Example 191 and 2- fluoroethanamine hydrochloride 241 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 576 for Example 191 and 1- dichloro-5-methyl-1H-pyrrol- C₂₃H₃₁Cl₂N₅O₆S; amino-2- 2-yl)carbonyl]amino}-3- NMR: 1.11 (s, 6H) 1.22 (d, 3 methylpropan-2-ol methoxypiperidin-1-yl)-4- H) 1.75 (s, 2H) 2.18 (s, 3H) {[(2-hydroxy-2- 3.14 (s, 3H) 3.38 (s, 3H) methylpropyl)amino]carbonyl}- 3.55 (s, 1H) 3.95 (s, 1H) 1,3-thiazole-5-carboxylate 4.17 (s, 2H) 4.27 (s, 2H) 4.39 (s, 1H) 7.14 (s, 1H) 8.28 (s, 1H) 12.17 (s, 1H)

Examples 242-245

The following Examples were prepared by the procedure described in Example 34 from the starting materials (SM) indicated.

Ex Compound Data SM 242 Cis(±)-ethyl 4-(aminocarbonyl)- MS (ES) MH⁺: 504 for Example 178 2-(4-{[(3,4-dichloro-5-methyl- C₁₉H₂₃Cl₂N₅O₅S 1H-pyrrol-2-yl)carbonyl]amino}- 3-methoxypiperidin-1-yl)-1,3- thiazole-5-carboxylate 243 ethyl 4-(aminocarbonyl)-2- MS (ES) MH⁺: 504 for Example 209 ((3R,4S)-4-{[(3,4-dichloro-5- C₁₉H₂₃Cl₂N₅O₅S methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-5-carboxylate 244 ethyl 4-(aminocarbonyl)-2- MS (ES) MH⁺: 492 for Example 210 ((3S,4R)-4-{[(3,4-dichloro-5- C₁₈H₂₀Cl₂FN₅O₄S methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylate 245 ethyl 4-(aminocarbonyl)-2- ((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 504 for C₁₉H₂₃Cl₂N₅O₅S NMR: 1.22 (t, 3H) 1.74 (d, 2H) 2.18 (s, 3H) 3.31 (s, 1H) 3.37 (s, 3H) 3.38-3.43 (m, 1H) 3.55 (s, 1H) 3.95 (s, 1H) 4.17 (q, 2H) 4.27 (s, 2H) 7.15 (d, 1H) 7.53 (s, 1H) 7.82 (s, 1H) 12.17 (s, 1H) Example 213

Example 246 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(morpholin-4-ylmethyl)-1,3-thiazole-5-carboxylate

To a solution of ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate (0.15 g, 0.31 mmol, Example 252) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.1 g, 0.47 mmol) and morpholine (0.03 mL, 0.34 mmol). Reaction was stirred at room temperature and monitored by LCMS. Upon completion, the reaction mixture was diluted with 1N HCl and then partitioned with EtOAc/sat. sodium bicarbonate. Washing with brine, drying with MgSO₄ and concentrating yielded a solid. Purification by silica gel flash column (gradient elution 70-100% EtOAc/CH₂Cl₂) afforded pure product (0.091 g) MS (ES) M+H⁺: 560 for C₂₃H₃₁Cl₂N₅O₅S; NMR: 1.24 (t, 3 H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.32 (s, 2 H) 3.36 (s, 3 H) 3.52 (s, 2 H) 3.54 (d, 4 H) 3.65-3.75 (m, 2 H) 3.76-3.86 (m, 2 H) 3.93 (s, 1 H) 4.18 (q, 2 H) 4.27 (s, 1 H) 7.16 (d, 1 H) 12.16 (s, 1 H).

Examples 247-249

The following Examples were prepared by the procedure described in Example 246 from the starting materials (SM) indicated.

Ex Compound Data SM 247 Cis(±)-ethyl 4-[(tert- MS (ES) MH⁺: 546 for Example 252 butylamino)methyl]-2-(4-{[3,4- C₂₃H₃₃Cl₂N₅O₄S; and tert- dichloro-5-methyl-1H-pyrrol-2- NMR: 1.04 (s, 9 H) 1.22 (t, 3 H) butylamine yl)carbonyl]amino}-3- 1.72 (d, 2 H) 2.17 (s, 3 H) methoxypiperidin-1-yl)-1,3- 3.32 (s, 1 H) 3.35 (s, 3 H) 3.53 (s, 1 thiazole-5-carboxylate H) 3.78-3.92 (m, 2 H) 4.17 (q, 2 H) 4.23 (d, 2 H) 7.14 (d, 1 H) 248 Cis(±)-ethyl 2-(4-{[(3,4- MS (ES) MH⁺: 558 for Example 252 dichloro-5-methyl-1H-pyrrol-2- C₂₄H₃₃Cl₂N₅O₄S and piperidine yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- (piperidin-1-ylmethyl)-1,3- thiazole-5-carboxylate 249 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 560 for Example 252 dichloro-5-methyl-1H-pyrrol-2- C₂₃H₃₁Cl₂N₅O₅S and pyrrolidin- yl)carbonyl]amino}-3- 3-ol methoxypiperidin-1-yl)-4-[(3- hydroxypyrrolidin-1-yl)methyl]- 1,3-thiazole-5-carboxylate

Example 250 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(E)-(hydroxyimino)methyl]-1,3-thiazole-5-carboxylate

A solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole -5-carboxylate (0.10 g, 0.2 mmol, Example 252), sodium acetate (0.041 g, 0.5 mmol) and hydroxylamine hydrochloride (0.028 g, 0.4 mmol) were heated to reflux in absolute ethanol for 3 hours. After cooling to room temperature the ethanol was removed under reduced pressure followed by EtOAc/H₂O partitioning, drying with MgSO4 and concentrating to a yellow solid (0.081 g) MS (ES): 504 NMR: 1.25 (t, 3H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.31 (s, 3 H) 3.36 (s, 3 H) 3.55 (s, 1 H) 3.95 (s, 1 H) 4.18-4.26 (m, 2 H) 4.26 (d, 2 H) 7.16 (d, 1 H) 8.61 (s, 1 H) 11.72 (s, 1 H) 12.16 (s, 1 H).

Example 251

The following Example was prepared by the procedure described in Example 250 from the starting materials (SM) indicated.

Ex Compound Data SM 251 ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 518 for Example 252 dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₅Cl₂N₅O₅S; and yl)carbonyl]amino}-3- NMR: 1.25 (t, 3 H) 1.76 (s, 2 H) methoxylamine methoxypiperidin-1-yl)-4-[(E)- 2.19 (s, 3 H) 3.30-3.32 (m, 2 H) hydrochloride (methoxyimino)methyl]-1,3- 3.35-3.39 (m, 3 H) 3.57 (s, 1 H) thiazole-5-carboxylate 3.92 (s, 3 H) 4.04 (s, 1 H) 4.19-4.25 (m, 2 H) 4.25-4.33 (m, 2 H) 7.16 (d, 1 H) 8.66 (s, 1 H) 12.16 (s, 1 H)

Example 252 Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate

To a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (0.63 g, 1.3 mmol, Example 143) in methylene chloride was added Dess-Martin periodinane (0.61 g, 1.4 mmol). After 1 hr stirring at room temperature the reaction was complete. The crude reaction mixture was washed with water (×2) and brine, followed by drying with MgSO4 and concentrating to a minimal volume of methylene chloride after which it was directly deposited on a silica gel flash column (gradient elution to 1:1 EtOAc in CH2 Cl2). Pure fractions concentrated to clean, yellow solid (0.56 g). NMR: 1.29 (t, 3 H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.38 (s, 4 H) 3.44 (s, 1 H) 3.57 (s, 1 H) 4.03 (d, 1H) 4.22-4.35 (m, 4 H) 7.15 (d, 1 H) 10.31 (s, 1 H) 12.16 (s, 1 H).

Example 253 ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(difluoromethyl)-1,3-thiazole-5-carboxylate

Diethylaminosulfurtrifluoride (0.03 mL, 0.22 mmol) was added to a solution of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate (0.10 g, 0.2 mmol, Example 252) in methylene chloride. The reaction was complete after heating at reflux overnight. Upon cooling to room temperature, the reaction was washed with water (×3) and brine (×1), dried with MgSO₄ and concentrated to a yellow solid which, upon trituration, yielded a clean white solid (0.021 g). MS (ES) M+H: 511 for C₁₉H₂₂Cl₂F₂N₄O₄S; NMR: 1.26 (t, 3 H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.37 (s, 3 H) 3.43 (s, 1 H) 3.56 (s, 1 H) 3.96 (s, 1 H) 4.25 (s, 1 H) 4.36 (s, 2 H) 7.16 (s, 1 H) 7.31 (s, 1 H) 12.17 (s, 1 H).

Example 254 ethyl 4-(azidomethyl)-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate

To a suspension of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (0.10 g, 0.2 mmol, Example 143) in anhydrous toluene was added diphenylphosphorylazide (0.053 mL, 0.24 mmol). The reaction was cooled to 0 deg and DBU was added slowly. After stirring at 0 deg for 30 min the reaction was warmed to room temperature and stirred overnight. The biphasic reaction mixture was washed with water (×3), 1NHCl (×1), brine (×1), dried with MgSO4 and concentrated (0.048 g). MS (ES) M+H: 516 for C₁₉H₂₃Cl₂N₇O₄S.

Example 255 Cis(±)-ethyl 4-[cyano(morpholin-4-yl)methyl]-2-(4-{[3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate

A solution of sodium cyanide (0.011 g, 0.22 mmol) and morpholine (0.018 mL, 0.21 mmol) in water (5 mL) was cooled to 0 deg. 1N HCl (0.22 mL, 0.22 mmol) was added slowly. After warming to room temperature, a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate (0.10 g, 0.2 mmol, Example 252) in methanol (10 mL) was added. After stirring at room temperature for six weeks the reaction was complete. The reaction mixture was concentrated to remove methanol and the residue was diluted with water and extracted with EtOAc (×3), washed with brine (×1), dried with MgSO₄ and concentrated to a pink solid (0.055 g). MS (ES) M+H: 585 for C₂₄H₃₀Cl₂N₆O₅S.

Example 256 ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[2-(methylsulfonyl)ethyl]amino}carbonyl) -1,3-thiazole-5-carboxylate

m-CPBA (0.091 g, 0.37 mmol) was added to a cold solution of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-({[2-(methylthio)ethyl]amino}carbonyl)-1,3-thiazole-5-carboxylate (0.107 g, 0.18 mmol, Example 238) in methylene chloride. After stirring at room temperature for 2 hours, the reaction mixture was washed with sat. sodium bicarbonate (×3), dried with MgSO4, and concentrated to a white solid (0.092 g). MS (ES) M+H: 610 for C₂₂H₂₉Cl₂N₅O₇S₂; NMR: 1.21 (q, 3H) 1.66-1.80 (m, 2 H) 2.18 (s, 3 H) 3.04 (s, 3 H) 3.29 (s, 4 H) 3.36 (s, 3 H) 3.51-3.62 (m, 3 H) 3.99 (s, 1 H) 4.17 (q, 2 H) 4.28 (s, 2 H) 7.15 (d, 1 H) 8.72 (t, 1 H) 12.17 (s, 1 H).

Examples 257-381

The following Examples were synthesized by an analogous method to Example 35 from the starting materials (SM) given in the table below.

Ex Compound NMR m/z SM 257 Cis(±)-2-{4-{[(3,4-dichloro-5- 1.85 (m, 2H), 2.16 (s, 3H), 2.2 479 Example 89 methyl-1H-pyrrol-2- (m, 1H), 2.5 (s, 3H), 2.6-2.9 (m, yl)carbonyl]amino}-3- 2H), 3.0 (m, 1H), 3.2 (m, 1H), 3.9 [(methylsulfinyl)methyl]piperidin- (m, 2H), 4.17 (m, 1H), 7.4 (s, 1-yl}-1,3-thiazole-5- 1H), 7.7 (dd. 1H), 7.9 (broad s, 1H). carboxylic acid 258 Cis(±)-2-{4-{[(3,4-dichloro-5- 1.71 (m, 2H), 2.12 (s, 3H), 2.96 496 Example 90 methyl-1H-pyrrol-2- (s, 3H), 2.99 (m, 2H), 3.12 (m, yl)carbonyl]amino}-3- 3H), 3.95 (m, 2H), 4.3 (m, 1H), [(methylsulfonyl)methyl]piperidin- 7.37 (d, 1H), 7.7 (s, 1H), 12 1-yl}-1,3-thiazole-5- (broad s, 1H), 12.6 (broad s, 1H). carboxylic acid 259 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.75 (m, 2H), 2.12 (s, 3H), 2.45 435 Example 91 methyl-1H-pyrrol-2- (s, 3H), 3.14 (m, 1H), 3.27 (dd, yl)carbonyl]amino}-3- 1H), 3.8 (d, 1H), 4.0 (m, 2H), fluoropiperidin-1-yl)-5-methyl- 4.78 (d, 1H), 5.9 (broad s, 1H), 1,3-thiazole-4-carboxylic acid 7.16 (d, 1H), 12 (s, 1H). 260 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-5- methyl-1,3-thiazole-4- carboxylic acid

1.67 (m, 2H), 2.1 (s, 3H), 2.45 (s, 3H), 3.1 (m, 2H), 3.3 (s, 3H), 3.7 (d, 2H), 4.0 (dd, 2H), 4.4 (broad s, 1H), 7.0 (d, 1H), 12.1 (s, 1H). 447 Example 92 261 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.86 (m, 4H), 2.2 (s, 6H), 3.4 (m, 478 Example 94 methyl-1H-pyrrol-2- 4H), 3.8 (s, 3H), 3.9 (s, 3H), 4.0 yl)carbonyl]amino}-3- (m, 2H), 4.3 (m, 4H), 4.9 (s, 1H), fluoropiperidin-1-yl)-5- 5.0 (s, 1H), 7.2 (d, 2H), 8.4 (s, [(methoxyimino)methyl]-1,3- 1H), 8.7 (s, 1H), 12.1 (s, 2H), thiazole-4-carboxylic acid 13.2 (s, 2H). 262 Cis(±)-2-[4-{[(3,4-dichloro-5- 1.93 (m, 2H), 2.16 (s, 3H), 3.3- 566 Example 93 methyl-1H-pyrrol-2- 3.8 (m, 11H), 4.0 (m, 2H), 4.4 (m, yl)carbonyl]amino}-3- 1H), 7.2 (d, 1H), 7.4 (t, 1H), 7.6 (morpholin-4- (d, 1H), 7.7 (d, 1H), 9.8 (broad s, ylcarbonyl)piperidin-1-yl]- 1H), 12.0 (s, 1H). 1,3-benzothiazole-7- carboxylic acid 263 Cis(±)-2-[4-{[(3,4-dichloro-5- 1.65-1.90 (m, 2H); 2.14 (s, 3H); 449 Example 95 methyl-1H-pyrrol-2- 2.19 (s, 3H); 3.20-3.45 (m, 2H); yl)carbonyl]amino}-3- 3.73 (d, 1H); 3.94 (d, 1H); 4.02 (methylthio)piperidin-1-yl]- (dd, 1H); 4.43 (m, 1H); 7.24 (d, 1,3-thiazole-5-carboxylic acid 1H); 7.75 (s, 1H); 12.13 (s, 1H); 12.66 (s, 1H). 264 Cis(±)-2-[4-{[(3,4-dichloro-5- 1.70 (m, 1H); 1.90 (m, 1H); 2.11 481 Example 96 methyl-1H-pyrrol-2- (s, 3H); 3.00 (s, 3H); 3.30-3.45 yl)carbonyl]amino}-3- (m, 2H); 3.45 (m, 1H); 3.62 (m, (methylsulfonyl)piperidin-1- 2H); 4.30 (bd, 1H); 7.39 (s, 1H); yl]-1,3-thiazole-5-carboxylic 8.20 (m, 1H); 12.10 (s, 1H); acid 12.60 (s, 1H). 265 Cis(±)2-(3-(benzyloxy)-4- {[(3,4-dichloro-5-methyl-1H- pyrrol-2- yl)carbonyl]amino}piperidin-1- yl)-1,3-thiazole-5-carboxylic acid

1.79 (m, 2H); 2.18 (s, 3H); 3.35 (m, 2H); 3.81 (s, 1H); 3.95 (d, 1H); 4.29 (m, 1H); 4.46 (m, 2H); 4.71 (d, 1H); 7.09 (d, 1H); 7.25 (s, 5H); 7.75 (s, 1H); 12.12 (s, 1H); 12.63 (s, 1H). 509 Example 97 266 Cis(±)-2-[4-{[(3,4-dichloro-5- 1.76 (m, 2H); 2.18 (s, 3H); 3.30 457 Example 98 methyl-1H-pyrrol-2- (m, 2H); 3.44 (t, 1H); 3.87 (s, yl)carbonyl]amino}-3-(prop-2- 1H); 3.96 (m, 1H); 4.22-4.36 (m, yn-1-yloxy)piperidin-1-yl]-1,3- 4H); 7.15 (d, 1H); 7.73 (s, 1H); thiazole-5-carboxylic acid 12.15 (s, 1H); 12.62 (s, 1H). 267 Trans(±)2-(3-(benzyloxy)-4- 1.72 (m, 1H), 1.98 (m, 1H), 2.17 509 Example 99 {[(3,4-dichloro-5-methyl-1H- (s, 3H), 3.26 (m, 1H), 3.67 (m, and benzyl pyrrol-2- 1H), 3.82 (m, 1H), 4.14 (m, 2H), bromide yl)carbonyl]amino}piperidin-1- 4.63 (dd, 2H), 7.28 (m, 5H), 7.34 yl)-1,3-thiazole-5-carboxylic (d, 2H), 7.76 (s, 1H), 12.00 (s, acid 1H), 12.66 (br s, 1H) 268 Trans(±)2-(3-(allyloxy)-4- 1.67 (m, 1H), 1.98 (m, 1H), 2.17 459 Example 99 {[(3,4-dichloro-5-methyl-1H- (s, 3H), 3.22 (m, 1H), 3.37 (m, and allyl pyrrol-2- 1H), 3.57 (m, 1H), 3.79 (m, 1H), bromide yl)carbonyl]amino}piperidin-1- 4.09 (m, 4H), 5.10 (d, 1H), 5.23 yl)-1,3-thiazole-5-carboxylic (dd, 1H), 5.85 (m, 1H), 7.31 (d, acid 2H), 7.76 (s, 1H), 11.99 (s, 1H) 269 Trans(±)2-(4-{[(3,4-dichloro-5- 1.60 (m, 1H), 2.01 (m, 1H), 2.17 419 Example 99 methyl-1H-pyrrol-2- (s, 3H), 3.07 (m, 1H), 3.30 (m, yl)carbonyl]amino}-3- 1H), 3.61 (m, 1H), 3.82 (m, 1H), hydroxypiperidin-1-yl)-1,3- 3.90 (m, 1H) 3.99 (m, 1H), 4.58 thiazole-5-carboxylic acid (m, 1H), 7.18 (d, 1H), 7.31 (m, 1H), 7.75 (s, 1H), 11.97 (s, 1H) 270 Trans(±)2-[4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3-(pyridin- 2-ylmethoxy)piperidin-1-yl]- 1,3-thiazole-5-carboxylic acid

1.74 (m, 1H), 2.00 (m, 1H), 2.16 (s, 3H), 3.36 (m, 2H), 3.79 (m, 2H), 4.18 (m, 2H), 4.80 (dd, 2H), 7.41 (brd, 1H), 7.46 (brt, 2H), 7.54 (brd, 1H), 7.76 (s, 1H), 7.94 (brt, 1H), 8.58 (brd, 1H), 11.99 (s, 1H) 510 Example 99 and 2- chloromethyl- pyridine 271 2-((3S,4R)-4-{[(3-chloro-5- 1.85 (m, 2H); 2.17 (s, 3H); 3.48 387 Example 100 methyl-1H-pyrrol-2- (m 2H); 4.0 (m, 1H); 4.33 (m, yl)carbonyl]amino}-3- 2H); 4.96 (d, br, 1H); 5.95 (s, fluoropiperidin-1-yl)-1,3- 1H); 7.10 (d, 1H); 7.76 (s, 1H); thiazole-5-carboxylic acid 11.63 (s, 1H); 12.68 (s, br, 1H) 272 2-((3S,4R)-4-{[(3-chloro-5- 1.88 (m, 2H); 2.17 (s, 3H); 3.31 387 Example 101 methyl-1H-pyrrol-2- (m 2H); 3.94 (m, 1H); 4.23 (m, yl)carbonyl]amino}-3- 2H); 4.90 (d, br, 1H); 5.93 (s, fluoropiperidin-1-yl)-1,3- 1H); 7.10 (d, 1H); 7.62 (s, 1H); thiazole-4-carboxylic acid 11.62 (s, 1H) 273 2-((3S,4R)-4-{[(3-chloro-5- 1.88 (m, 2H); 2.17 (s, 3H); 3.31 437 Example 102 methyl-1H-pyrrol-2- (m 2H); 4.19 (m, 1H); 4.46 (m, yl)carbonyl]amino}-3- 2H); 4.97 (d, br, 1H); 5.93 (s, fluoropiperidin-1-yl)-1,3- 1H); 7.10 (d, 1H); 7.41 (t, 1H); benzothiazole-7-carboxylic 7.68 (d, 1H); 7.69 (d, 1H); 11.62 acid (s, 1H) 274 2-((3S,4R)-4-{[(3-chloro-5- 1.80 (m, 2H); 2.16 (s, 3H); 3.06 381 Example 108 methyl-1H-pyrrol-2- (m 2H); 4.40 (m, 2H); 4.71 (m, yl)carbonyl]amino}-3- 1H); 4.90 (d, br, 1H); 5.94 (s, fluoropiperidin-1- 1H); 7.03 (m, 2H); 7.26 (s, 1H); yl)isonicotinic acid 8.22 (d, 1H); 11.61 (s, br, 1H) 275 2-((3S,4R)-4-{[(4-bromo-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylic acid

1.94 (m, 1H); 1.98 (m, 1H); 2.14 (s, 3H); 3.31 (m 2H); 4.01 (m, 1H); 4.28 (m, 2H); 4.86 (d, br, 1H); 6.94 (s, 1H); 7.75 (s, 1H); 8.02 (d, 1H); 11.73 (s, 1H). 432 Example 103 276 2-((3S,4R)-4-{[(4-bromo-5- 1.72 (m, 1H); 1.92 (m, 1H); 2.15 426 Example 109 methyl-1H-pyrrol-2- (s, 3H); 3.10 (m, 1H); 3.30 (m, yl)carbonyl]amino}-3- 1H); 4.24 (m, 1H); 4.44 (m, 1H); fluoropiperidin-1- 4.69 (m, 1H); 4.86 (d, br, 1H); yl)isonicotinic acid 6.96 (s, 1H); 7.05 (d, 1H); 7.33 (s, 1H); 7.95 (d, 1H); 8.24 (d, 1H); 11.74 (s, br, 1H). 277 2-((3S,4R)-4-{[(4-bromo-3- 1.86 (m, 2H); 2.19 (s, 3H); 3.48 466 Example 104 chloro-5-methyl-1H-pyrrol-2- (m 1H); 3.53 (m, 1H); 4.01 (m, yl)carbonyl]amino}-3- 1H); 4.33 (m, 2H); 4.96 (d, br, fluoropiperidin-1-yl)-1,3- 1H); 7.32 (d, 1H); 7.76 (s, 1H); thiazole-5-carboxylic acid 12.24 (s, 1H); 12.69 (br, 1H). 278 2-((3S,4R)-4-{[(4-bromo-3- 1.85 (m, 2H); 2.19 (s, 3H); 3.31 466 Example 105 chloro-5-methyl-1H-pyrrol-2- (m 2H); 3.95 (m, 1H); 4.23 (m, yl)carbonyl]amino}-3- 2H); 4.90 (d, br, 1H); 7.45 (d, fluoropiperidin-1-yl)-1,3- 1H); 7.63 (s, 1H); 12.39 (s, br, thiazole-4-carboxylic acid 1H). 279 2-((3S,4R)-4-{[(4-bromo-3- 1.86 (m, 2H); 2.19 (s, 3H); 3.29 510 Example 107 chloro-5-methyl-1H-pyrrol-2- (s, 2H); 3.60 (m 2H); 4.04 (m, yl)carbonyl]amino}-3- 1H); 4.30 (m, 2H); 4.57 (s, 3H); fluoropiperidin-1-yl)-4- 4.90 (d, br, 1H); 7.32 (d, 1H); (methoxymethyl)-1,3-thiazole- 12.25 (s, 1H); 12.78 (br, 1H) 5-carboxylic acid 280 2-((3S,4R)-4-{[(4-bromo-3- chloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1- yl)isonicotinic acid

1.86 (m, 2H); 2.19 (s, 3H); 3.07 (m, 1H); 4.04 (m, 1H); 4.28 (m, 2H); 4.69 (m, 1H); 4.90 (d, br, 1H); 7.01 (d, 1H); 7.27 (s, 1H); 7.82 (m, 1H); 8.02 (m, 1H); 13.38 (s, br, 1H) 460 Example 106 281 Cis(±)-2-[4-{[(3,4-Dichloro-5- 1.74-1.76 (m, 2H), 2.17 (s, 3H), 477 Example 110 methyl-1H-pyrrol-2- 3.14 (s, 3H), 3.25-3.42 (m, 4H), yl)carbonyl]amino}-3-(2- 3.50-3.60 (m, 1H), 3.67-3.73 (m, methoxyethoxy)piperidin-1- 2H), 3.75-4.00 (m, 2H), 4.20- yl]-1,3-thiazole-5-carboxylic 4.35 (m, 2H), 7.14 (d, 1H), 7.72 acid (s, 1H), 12.14 (brs, 1H) 282 Cis(±)-2-[4-{[(3,4-Dichloro-5- 1.74-1.80 (m, 2H), 2.17 (s, 3H), 477 Example 111 methyl-1H-pyrrol-2- 3.14 (s, 3H), 3.25-3.42 (peaks yl)carbonyl]amino}-3-(2- overlapping with H₂O signal), methoxyethoxy)piperidin-1- 3.50-3.60 (m, 1H), 3.67-3.73 (m, yl]-1,3-thiazole-4-carboxylic 2H), 3.86-3.90 (m, 1H), 4.12- acid 4.35 (m, 2H), 7.15 (d, 1H), 7.57 (s, 1H), 12.13 (brs, 1H), 12.55 (brs, 1H) 283 Cis(±)-2-[4-{[(3,4-Dichloro-5- 1.70-1.75 (m, 2H), 2.17 (s, 3H), 471 Example 113 methyl-1H-pyrrol-2- 3.05-3.20 (m, 2H), 3.09 (s, 3H), yl)carbonyl]amino}-3-(2- 3.25-3.35 (m, 2H), 3.45--3.73 methoxyethoxy)piperidin-1- (peaks overlapping with H₂O yl]isonicotinic acid signal), 4.20-4.25 (m, 2H), 4.60- 4.70 (m, 1H), 6.97 (d, 1H), 7.13 (d, 1H), 7.26 (s, 1H), 8.19 (d, 1H), 12.13 (s, 1H) 284 Cis(±)-2-[4-{[(3,4-Dichloro-5- 1.79-1.75 (m, 2H), 2.19 (s, 3H), 527 Example 114 methyl-1H-pyrrol-2- 3.12 (s, 3H), 3.27-3.45 (peaks yl)carbonyl]amino}-3-(2- overlapping with H₂O signal), methoxyethoxy)piperidin-1- 3.51-3.62 (m, 1H), 3.72-3.80 (m, yl]-1,3-benzothiazole-7- 2H), 4.05-4.13 (m, 1H), 4.24-4.42 carboxylic acid (m, 2H), 7.18 (d, 1H), 7.39 (t, 1H), 7.65 (t, 2H), 12.16 (s, 1H), 13.48 (brs, 1H) 285 Cis(±)-2-[4-{[(3,4-Dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3-(2- methoxyethoxy)piperidin-1- yl]-4-methyl-1,3-thiazole-5- carboxylic acid

1.70-1.75 (m, 2H), 2.17 (s, 3H), 2.39 (s, 3H), 3.15 (s, 3H), 3.32- 3.40 (m, buried under water peak), 3.50-3.60 (m, 1H), 3.68- 3.75 (m, 2H), 3.86-3.98 (m, 1H), 4.20-4.30 (m, 2H), 7.14 (d, 1H), 12.14 (s, 1H), 12.38 (brs, 1H) 490 Example 112 286 2-((3S,4R)-4-{[(4-chloro-1H- 1.62-1.76 (m, 1H), 1.85-2.03 (m, 373 Example 115 pyrrol-2-yl)carbonyl]amino}-3- 1H), 3.22 (s, 3H), 3.36-3.45 (m, fluoropiperidin-1-yl)-1,3- 1H), 3.50 (dd, 1H), 3.75 (s, 1H), thiazole-5-carboxylic acid 4.02-4.10 (m, 1H), 4.15-4.36 (m, 2H), 4.90 (d, 1H), 6.94-6.97 (m, 2H), 7.85 (s, 1H), 8.10 (d, 1H), 11.82 (s, 1H) 287 2-((3S,4R)-4-{[(4-chloro-5- 1.62-1.74 (m, 1H), 1.84-2.05 (m, 401 Example 116 methyl-1H-pyrrol-2- 1H), 2.13 (s, 3H), 2.41 (s, 3H), yl)carbonyl]amino}-3- 3.19-3.30 (m, 1H), 3.50 (dd, 1H), fluoropiperidin-1-yl)-4-methyl- 3.96-4.02 (m, 1H), 4.20-4.31 (m, 1,3-thiazole-5-carboxylic acid 2H), 4.87 (d, 1H), 6.89 (d, 1H), 7.97 (d, 1H), 11.65 (s, 1H) 288 2-((3S,4R)-4-{[(4-chloro-1H- 1.68-1.74 (m, 1H), 1.85-2.00 (m, 387 Example 117 pyrrol-2-yl)carbonyl]amino}-3- 1H), 2.39 (s, 3H), 3.30-3.54 fluoropiperidin-1-yl)-4-methyl- (peaks buried under water peak), 1,3-thiazole-5-carboxylic acid 3.94-4.00 (m, 1H), 4.10-4.32 (m, 2H), 4.82 (d, 1H), 6.94-6.97 (m, 2H), 8.11 (d, 1H), 11.84 (s, 1H) 289 2-((3S,4R)-4-{[(4,5-dichloro- 1.69-1.74 (m, 1H), 1.86-2.00 (m, 419 Example 118 1H-pyrrol-2- 1H), 2.40 (s, 3H), 3.25-3.35 (m, yl)carbonyl]amino}-3- 1H, buried under water peak), fluoropiperidin-1-yl)-4-methyl- 3.51 (dd, 1H), 3.96-4.00 (m, 1H), 1,3-thiazole-5-carboxylic acid 4.16-4.31 (m, 2H), 4.87 (d, 1H), 7.06 (d, 1H), 8.15 (d, 1H), 12.48 (brs, 1H), 12.78 (s, 1H) 290 2-((3S,4R)-4-{[(4,5-Dichloro- 1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylic acid

1.64-1.74 (m, 1H), 1.85-2.00 (m, 1H), 3.30-3.40 (m, 1H, buried under water peak), 3.53 (dd, 1H), 4.00-4.08 (m, 1H), 4.12-4.40 (m, 2H), 4.89 (d, 1H), 7.06 (d, 1H), 7.75 (s, 1H), 8.16 (d, 1H), 12.78 (s, 1H) 405 Example 119 291 Cis(±)-2-[4-{[(3,4-dichloro-5- 0.95 (d, 3H), 1.73-1.85 (m, 2H), 477 Example 120 methyl-1H-pyrrol-2- 2.16 (s, 3H), 3.19-3.36 (m, 6 H, yl)carbonyl]amino}-3-(2- broad peaks), 3.61-3.67 (m, 3H), hydroxypropoxy)piperidin-1- 3.94-4.30 (m, difficult to integrate yl]-1,3-thiazole-5-carboxylic as the peaks are buried under acid water peak), 7.16 (d, 1H), 7.71 (s, 1H), 12.11 (s, 1H) 292 Cis(±)-2-[4-{[(3,4-dichloro-5- 0.96 (d, 3H), 1.73-1.76 (m, 2H), 491 Example 121 methyl-1H-pyrrol-2- 2.17 (s, 3H), 3.14 (s, 1H), 3.28- yl)carbonyl]amino}-3-(2- 3.67 (difficult to integrate as the methoxypropoxy)piperidin-1- peaks are buried under water yl]-1,3-thiazole-5-carboxylic peak), 3.89-3.92 (m, 1H), 4.20- acid 4.45 (m, 2H), 7.12 (d, 1H), 7.72 (s, 1H), 12.15 (s, 1H) 293 2-((3R,4S)-4-{[(3,4-dichloro-5- 1.85 (m, 2H), 2.25 (s, 3H), 3.41- 483 Example 123 methyl-1H-pyrrol-2- 3.48 (m, 6H), 4.16 (m, 1H), 5.35 yl)carbonyl]amino}-3- (m, 1H), 4.41 (m, 1H), 7.26 (d, methoxypiperidin-1-yl)-1,3- 1H), 7.49 (t, 1H), 7.72 (t, 2H0, benzothiazole-7-carboxylic 12.23 (s, 1H) 294 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.85 (m, 2H), 2.25 (s, 3H), 3.41- 483 Example 122 methyl-1H-pyrrol-2- 3.48 (m, 6H), 4.16 (m, 1H), 5.35 yl)carbonyl]amino}-3- (m, 1H), 4.41 (m, 1H), 7.26 (d, methoxypiperidin-1-yl)-1,3- 1H), 7.49 (t, 1H), 7.72 (t, 2H), benzothiazole-7-carboxylic acid 12.23 (s, 1H) 295 Cis(±)2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-4-carboxylic acid

1.74 (m, 2H), 2.10 (s, 3H), 3.29 (m, 1H), 3.48 (d, 1H), 3.85 (d, 1H), 4.14 (m, 1H), 4.29 (m, 1H), 4.83 (d, 1H), 7.18 (d, 1H), 7.53 (s, 1H), 12.03 (s, 1H) 421 Example 124 296 2-((3S,4R)-4-{[(4-chloro-5- 1.85 (m, 1H), 2.14 (m, 1H), 2.23 449 Example 125 methyl-1H-pyrrol-2- (s, 3H), 3.33 (s, 3H), 3.62-3.81 yl)carbonyl]amino}-3- (m, 2H), 4.29 (m, 1H), 4.43 (m, methoxypiperidin-1-yl)-1,3- 1H), 4.51 (m, 1H), 7.09 (s, 1H), benzothiazole-7-carboxylic 7.59 (t, 1H), 7.82-7.90 (m, 2H), acid 11.84 (s, 1H) 297 Cis(±)2-(4-{[(4-chloro-3,5- 1.47 (m, 1H), 1.62 (m, 1H), 1.95 413 Example 126 dimethyl-1H-pyrrol-2- (s, 3H0, 1.98 (s, 3H), 3.13 (m, yl)carbonyl]amino}-3- 1H), 3.32 (m, 1H), 3.42 (s, 3H), methoxypiperidin-1-yl)-1,3- 3.68 (m, 1H), 4.04 (m, 2H), 6.89 thiazole-5-carboxylic acid (d, 1H), 7.53 (s, 1H), 11.22 (s, 1H) 299 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.74 (m, 2H), 2.10 (s, 3H), 3.29 421 Example 128 methyl-1H-pyrrol-2- (m, 1H), 3.48 (d, 1H), 3.85 (d, yl)carbonyl]amino}-3- 1H0, 4.14 (m, 1H), 4.29 (m, 1H), fluoropiperidin-1-yl)-1,3- 4.83 (d, 1H), 7.18 (d, 1H), 7.53 thiazole-4-carboxylic acid (s, 1H), 12.03 (s, 1H) 300 2-((3S,4R)-4-{[(4-chloro-3,5- 1.69 (m, 1H), 1.82 (m, 1H), 2.09 401 Example 129 dimethyl-1H-pyrrol-2- (s, 3H), 2.13 (s, 3H), 3.19-3.30 yl)carbonyl]amino}-3- (m, 2H), 3.89 (m, 1H), 4.14 (m, fluoropiperidin-1-yl)-1,3- 2H), 4.83 (d, 1H), 7.38 (d, 1H), thiazole-4-carboxylic acid 7.56 (s, 1H), 11.29 (s, 1H) 301 2-((3R,4S)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-4-carboxylic acid

1.74 (m, 2H), 2.10 (s, 3H), 3.29 (m, 1H), 3.48 (d, 1H), 3.85 (d, 1H0, 4.14 (m, 1H), 4.29 (m, 1H), 4.83 (d, 1H), 7.18 (d, 1H), 7.53 (s, 1H), 12.03 (s, 1H) 421 Example 130 302 Cis(±)2-(3-chloro-4-{[(3,4- 1.87 (m, 1H), 1.93 (m, 1H), 2.20 437 Example 131 dichloro-5-methyl-1H-pyrrol- (s, 3H), 3.41 (m, 1H), 3.82 (d, 2-yl)carbonyl]amino}piperidin- 1H), 4.01 (d, 1H), 4.27 (d, 1H), 1-yl)-1,3-thiazole-5-carboxylic 4.75 (s, 1H), 7.18 (d, 1H), 7.75 (s, acid 1H), 12.15 (s, 1H) 303 2-{(3S,4R)-4-[({4-chloro-3- 1.86 (m, 2H), 2.35 (s, 3H), 3.33 444 Example 132 [(E)-(methoxyimino)methyl]-5- (m, 1H), 3.61 (dd, 1H), 3.82 (s, methyl-1H-pyrrol-2- 3H), 4.00 (d, 1H), 4.34 (m, 2H), yl}carbonyl)amino]-3- 4.93 (d, 1H), 7.28 (d, 1H), 7.76 fluoropiperidin-1-yl}-1,3- (s, 1H), 8.02 (s, 1H), 12.14 (s, thiazole-5-carboxylic acid 1H), 12.66 (s, 1H) 304 Cis(±)-2-(3-chloro-4-{[(3,4- 1.82 (m, 2H), 2.25 (s, 3H), 3.41 489 Example 133 dichloro-5-methyl-1H-pyrrol- (m, 1H), 3.42 (m, 2H), 4.19 (m, 2-yl)carbonyl]amino}piperidin- 1H), 5.35 (m, 1H), 4.41 (m, 1H), 1-yl)[1,3]thiazolo[4,5- 7.28 (d, 1H), 7.43 (t, 1H), 7.72 (t, b]pyridine-7-carboxylic acid 2H), 12.23 (s, 1H) 305 Cis(±)-2-(3-chloro-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}piperidin- 1-yl)-4-(hydroxymethyl)-1,3- thiazole-5-carboxylic acid

1.84 (m, 1H), 1.91 (m, 1H), 2.20 (s, 3H), 3.33 (m, 1H), 3.79 (m, 1H), 4.04 (m, 1H), 4.21 (m, 1H), 4.48 (m, 1H), 4.59 (m, 2H), 4.75 (s, 1H), 7.20 (d, 1H), 12.17 (s, 1H) 468 Example 134 306 Cis(±)-2-(3-chloro-4-{[(4- 1.72 (m, 1H), 2.07 (m, 1H), 2.14 403 Example 135 chloro-5-methyl-1H-pyrrol-2- (s, 3H), 3.34 (t, 1H), 3.81 (d, 1H), yl)carbonyl]amino}piperidin-1- 4.03 (d, 1H), 4.22 (d, 1H), 4.36 yl)-1,3-thiazole-5-carboxylic (m, 1H), 4.73 (s, 1H), 6.91 (s, acid 1H), 7.75 (s, 1H), 7.95 (d, 1H), 11.70 (s, 1H) 307 Cis(±)-2-(3-chloro-4-{[(3,4- 1.83 (m, 1H), 1.92 (m, 1H), 2.20 481 Example 136 dichloro-5-methyl-1H-pyrrol- (s, 3H), 3.28 (s, 3H0, 3.35 (m, 2-yl)carbonyl]amino}piperidin- 1H), 3.80 (d, 1H), 4.01 (m, 1H), 1-yl)-4-(methoxymethyl)-1,3- 4.22 (m, 1H), 4.43 (m, 1H), 4.56 thiazole-5-carboxylic acid (m, 2H), 4.75 (s, 1H), 7.18 (d, 1H), 12.15 (s, 1H) 308 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.78 (m, 1H), 1.91 (m, 1H), 2.19 470 Intermediate methyl-1H-pyrrol-2- (s, 3H), 3.32 (m, 2H), 3.55 (d, 131 and 2- yl)carbonyl]amino}-3- 1H), 3.90 (s, 1H), 4.03 (m, 1H), bromo-1,3- hydroxypiperidin-1-yl)-1,3- 4.17 (m, 1H), 5.53 (d, 1H), 7.15 benzthiazole- benzothiazole-7-carboxylic (d, 1H), 7.41 (t, 1H), 7.64 (t, 2H), 7-carboxylate acid 12.15 (s, 1H), 13.47 (s, 1H) 309 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.65 (m, 1H), 1.8 (m, 1H), 2.2 (s, 500 Example 137 methyl-1H-pyrrol-2- 3H), 3.3 (m), 3.55 (s, 1H), 4.3 (m, yl)carbonyl]amino}-3- 1H), 7.1 (m 2H), 8.9 (s, 1H), 12.2 methoxypiperidin-1-yl)-5- (s, 1H), 13.9 (s, 1H) nitroisonicotinic acid 310 Cis(±)-2-(4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-5- [(methoxycarbonyl)amino] isonicotinic acid

1.7 (m, 2H), 2.2 (s, 3H), 2.4-2.5 (m), 3.0-3.2 (m 2H), 3.3 (s, 3H), 3.5 (m 1H), 3.6 (s, 3H), 4.1 (m, 1H), 4.2 (m, 1H), 4.5 (m, 1H), 7.1 (m, 2H), 8.6 (s, 1H), 12.1 (s, 1H), 13.7 (s, 1H) 500 Example 195 311 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.7 (m, 2H) 2.2 (s, 3H), 2.9 (s, 506 Example 196 methyl-1H-pyrrol-2- 3H), 3.1 (m, 2H), 3.3-3.5 (m), yl)carbonyl]amino}-3- 3.5 (m, 1H), 4.2 (m, 2H), 4.6 (d, methoxypiperidin-1-yl)-5- 1H), 7.1 (m, 2H), 8.1 (s, 1H), [(methylsulfonyl)amino]isonicotinic 12.1 (s, 1H). acid 312 Cis(±)-2-(4-{[(3,4-dichloro-5- 0.9 (d, 3H), 1.8 (m, 2H), 2.2 (m, 431 Example 138 methyl-1H-pyrrol-2- 4H), 3.3-3.8 (m, 4H), 4.25 (m, yl)carbonyl]amino}-3- 1H), 4.25 (m, 1H), 7.2 (d, 1H), methylpiperidin-1-yl)-1,3- 7.8 (s, 1H), 12.0 (s, 1H), 12.6 (s, thiazole-5-carboxylic acid 1H) 313 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.3 (d, 1H), 1.8-2.1 (m, 4H), 2.2 417; Example 139 methyl-1H-pyrrol-2- (s, 3H), 3.6 (m, 1H), 3.8 (m 1H), yl)carbonyl]amino}-2- 4.1 (m, 2H), 7.3 (s, 1H), 7.8 (s, methylpiperidin-1-yl)-1,3- 1H), 12.1 (s, 1H) thiazole-5-carboxylic acid 314 Cis(±)-2-(4-{[(3,4-dichloro-5- 0.9 (m, 1H), 1.3 (d, 6H), 1.7, (m, 441 Example 140 methyl-1H-pyrrol-2- 1H), 2.2 (s, 3H), 2.4 (s, 3H), 3.1 yl)carbonyl]amino}-3- (m, 2H), 3.5 (m, 1H), 4.2 (m, methoxypiperidin-1-yl)-6- 2H), 4.7 (d, 1H), 5.1 (m, 1H), 6.8 methylisonicotinic acid (s, 1H), 7.0 (s, 1H), 7.15 (s, 1H), 12.1 (s, 1H). 315 Cis(±)-5-chloro-4-(4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1- yl)pyridine-2-carboxylic acid

NMR: 1.8, (m, 3H), 2.2 (s, 3H), 3.3 (s, 3H), 3.6 (m, 2H), 4.0 (m, 1H), 4.2 (m, 1H), 7.2 (s, 1H), 7.7 (s, 1H), 8.5 (s, 1H), 12.1 (s, 1H), 12.4 (s, broad, 1H). 461 Example 141 316 2-((3S,4R)-4-{[(3,4-dichloro-5- NMR: 1.85 (m, 2H), 2.2 (s, 3H), 451 Example 142 methyl-1H-pyrrol-2- 3.3-3.7 (m, 2H), 4.0 (m, 1H), 4.3 and yl)carbonyl]amino}-3- (m, 2H), 4.6 (s, 2H), 4.95 (d, 1H), Intermediate fluoropiperidin-1-yl)-4- 7.3 (d, 1H), 12.1 (s, 1H), 12.7 (s, 215 (hydroxymethyl)-1,3-thiazole- 1H). 5-carboxylic acid 317 Cis(±)-2-(4-{[(3,4-dichloro-5- NMR: 1.2 (t, 3H), 1.7 (m, 2H), 463 Example 143 methyl-1H-pyrrol-2- 2.2 (s, 3H), 3.4 (s, 3H), 3.55 (m, yl)carbonyl]amino}-3- 1H), 4.0 (m, 1H), 4.1-4.4 (m, methoxypiperidin-1-yl)-4- 4H), 4.6 (s, 2H), 7.1 9d, 1H), 12.1 (hydroxymethyl)-1,3-thiazole- (s, 1H). 5-carboxylic acid 318 Cis(±)-2-(4-{[(4-chloro-3- NMR: 1.6-1.9 (m, 2H), 2.2 (s, 424 Example 144 cyano-5-methyl-1H-pyrrol-2- 3H), 3.3 (s, 3H), 3.6 (m, 1H), 3.7 yl)carbonyl]amino}-3- (s, 3H), 3.9 (m, 1H), 4.3 (m, 2H), methoxypiperidin-1-yl)-1,3- 7.75 (m, 2H), 12.6 (2s, 2H). thiazole-5-carboxylicacid 319 Cis(±)-2-(4-{[(4-chloro-3- NMR: 1.6-2.0 (m, 2H), 2.2 (s, 479 Example 145 cyano-5-methyl-1H-pyrrol-2- 3H), 3.3 (s, 3H), 3.4 (m, 1H), 3.6 yl)carbonyl]amino}-3- (s, 3H), 4.1 (m, 1H), 4.2-4.4 (m, methoxypiperidin-1-yl)-1,3- 2H), 7.4 (t, 1H), 7.65 (m, 2H), 7.8 benzothiazole-7-carboxylic acid (m, 1H), 12.6 (s, 1H), 13.5 (s, 1H). 320 Cis(±)-2-(4-{[(4-chloro-3- cyano-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-1,3- thiazole-5-carboxylic acid

NMR: 1.7 (m, 2H), 2.2 (s, 3H), 3.0-3.7 (m), 4.2 (m, 2H), 4.6 (m, 1H), 7.0 (s, 1H), 7.25 (s, 1H), 7.7 (s, 1H), 8.2 (s, 1H), 12.6 (s, 1H), 13.5 (s, 1H). 418 Example 146 322 2-((3S,4R)-4-{[(4-chloro-3- NMR: 1.9 (m, 2H), 2.2 (s, 3H), 462 Example 148 cyano-5-methyl-1H-pyrrol-2- 3.4 (m, 1H), 3.4 (m, 1H), 3.6 (s, yl)carbonyl]amino}-3- 3H), 4.1 (m, 1H), 4.3 (m, 1H), 4.4 fluoropiperidin-1-yl)-1,3- (q, 2H), 7.7 (m, 2H), 7.8 (m, 1H), benzothiazole-7-carboxylic acid 7.9 (t, 1H), 12.7 (s, 1H), 13.5 (s, 1H). 323 2-((3S,4R)-4-{[(4-chloro-3- NMR: 1.8 (m, 2H), 2.2 (s, 3H), 406 Example 149 cyano-5-methyl-1H-pyrrol-2- 3.0 (m, 2H), 3.3 (m), 4.0-4.5 (m, yl)carbonyl]amino}-3- 2H), 4.7 (m, 1H), 4.95 (d, 1H), fluoropiperidin-1- 7.0 9d, 1H), 7.3 (s, 1H), 8.05 (m, yl)isonicotinic acid 1H), 8.25 (d, 1H), 12.6 (s, 1H), 13.4 (s, 1H). 324 Cis(±)-2-(4-{[(3,4-dichloro-5- NMR: 1.7 (m, 2H), 2.2 (s, 3H), 546 Example 150 methyl-1H-pyrrol-2- 3.3 (m), 3.4 (m, 4H), 3.5 (m, 4H), yl)carbonyl]amino}-3- 3.8-3.9 (m, 1H), 4.0-4.2 (m, 4H), methoxypiperidin-1-yl)-5- 7.3 (s, 1H), 12.3 (s, 1H), 12.9 (s, (morpholin-4-ylcarbonyl)-1,3- 1H). thiazole-4-carboxylic acid 325 Cis(±)-6-cyano-4-(4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1- yl)pyridine-2-carboxylic acid

NMR: 1.7 (m, 2H), 2.1 (s, 3H), 3.3 (s, 3H), 3.45 (m, 1H), 4.0 (d, 1H), 4.2 (m, 1H), 4.4 (d, 1H), 7.0 (d, 1H), 7.5 (s, 1H), 7.7 (s, 1H), 12.1 (s, 1H), 13.3 (s, 1H). 452 Example 151 326 2-((3S,4R)-4-{[(3,5-dichloro-4- NMR: 1.8 (m, 2H), 1.9 (s, 3H), 421 Example 155 methyl-1H-pyrrol-2- 3.3 (m, 1H), 3.5 (dd, 1H), 4.0 (m, yl)carbonyl]amino}-3- 1H), 4.3 (m, 2H), 5.0 (d, 1H), fluoropiperidin-1-yl)-1,3- 7.35 (d, 1H), 7.8 (s, 1H), 12.6 (s, thiazole-5-carboxylic acid 1H), 12.7 (s, 1H). 327 4-acetyl-2-((3S,4R)-4-{[(3,4- NMR: 1.7 (m, 2H), 2.2 (s, 3H), 475 Example 157 dichloro-5-methyl-1H-pyrrol- 3.3 (s, 3H), 3.9 (m, 2H), 4.3 (m, 2-yl)carbonyl]amino}-3- 2H), 7.15 (m, 1H), 12.2 (s, 1H), methoxypiperidin-1-yl)-1,3- 13.2 (s, 1H). thiazole-5-carboxylic acid 328 2-((3S,4R)-4-{[(3,4-dichloro-5- NMR: 1.5 (s, 6H), 1.7 (m, 2H), 491 Example 158 methyl-1H-pyrrol-2- 2.2 (s, 3H), 3.3 (s, 3H), 3.5 (m, yl)carbonyl]amino}-3- 1H), 3.8 (m, 2H), 4.3 (m, 1H), 4.4 methoxypiperidin-1-yl)-4-(1- (m, 1H), 7.15 (d, 1H), 12.2 (s, hydroxy-1-methylethyl)-1,3- 1H). thiazole-5-carboxylic acid 329 2-((3S,4R)-4-{[(3,4-dichloro-5- NMR: 1.8 (m, 2H), 2.2 (s, 3H), 489 Example 159 methyl-1H-pyrrol-2- 3.3 (s, 3H), 3.6 (m, 1H), 4.0 (m, yl)carbonyl]amino}-3- 1H), 4.3 (m, 2H), 7.2 (d, 1H), 7.9 methoxypiperidin-1- (s, 1H), 12.2 (s, 1H), 13.1 (s, 1H). yl)thieno[2,3-d][1,3]thiazole-6- carboxylic acid 330 Cis(±)-2-(3- (cyclopropylmethoxy)-4- {[(3,4-dichloro-5-methyl-1H- pyrrol-2- yl)carbonyl]amino}piperidin-1- yl)-1,3-thiazole-5-carboxylic acid

0.10 (m, 2H), 0.38 (m, 2H), 0.91 (m, 1H), 1.75 (m, 1H), 2.17 (s, 3H), 3.15-3.43 (m, 4H), 3.67 (m, 1H), 3.92 (m, 1H), 4.26 (m, 2H), 7.14 (d, 1H), 7.72 (s, 1H), 12.16 (s, 1H), 12.60 (bs, 1H). 473 Example 160 331 2-[4-{[(3,4-dichloro-5-methyl- 1.80 (m, 2H), 2.16 (s, 3H), 3.40 515 Example 161 1H-pyrrol-2- (d, 2H), 3.94 (m, 2H), 4.33 (td, yl)carbonyl]amino}-3-(1,3- 1H), 4.46 (d, 1H), 4.81-4.99 (dd, thiazol-2-ylmethoxy)piperidin- 2H), 7.13 (d, 1H), 7.65 (d, 1H), 1-yl]-1,3-thiazole-5-carboxylic 7.69 (s, 1H), 7.71 (d, 1H), 12.12 acid (s, 1H), 12.60 (bs, 1H). 332 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.05 (t, 3H); 1.74 (m, 2H); 2.17 447, Example 162 methyl-1H-pyrrol-2- (s, 3H); 3.35-3.45 (m, 3H); 3.63- 449 yl)carbonyl]amino}-3- 3.73 (m, 2H); 3.97 (m, 1H); 4.25 ethoxypiperidin-1-yl)-1,3- (m, 2H); 7.12 (d, 1H); 7.72 (s, thiazole-5-carboxylic acid 1H); 12.16 (s, 1H); 12.55 (br s, 1H). 333 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.06 (t, 3H); 1.74 (m, 2H); 2.17 435, Example 163 methyl-1H-pyrrol-2- (s, 3H); 3.27 (m, 4H); 3.42 (m, 437 yl)carbonyl]amino}-3- 1H); 3.62-3.71 (m, 2H); 3.82 (m, ethoxypiperidin-1-yl)-4- 1H); 4.08-4.21 (overlapping m, (methoxymethyl)-1,3-thiazole- 3H); 4.55 (s, 2H); 6.64 (s, 1H); 5-carboxylic acid 7.11 (d, 1H); 12.16 (s, 1H). 334 2-((3S,4R)-4-{[(3,4-Dichloro- 1.83 (m, 2H); 2.18 (s, 3H); 2.40 435, Example 165 5-methyl-1H-pyrrol-2- (s, 3H); 3.32 (m, overlapping 437 yl)carbonyl]amino}-3- water); 3.50 (dd, 1H); 3.97 (m, fluoropiperidin-1-yl)-4-methyl- 1H); 4.21-4.31 (m, 2H); 4.93 (d, 1,3-thiazole-5-carboxylic acid 1H); 7.26 (d, 1H); 12.11 (s, 1H); 12.44 br s, 1H). 335 2-((3S,4R)-4-{[(3,4-Dichloro- 5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- methyl-1,3-thiazole-5- carboxylic acid

1.72 (m, 2H); 2.17 (s, 3H); 2.39 (s, 3H); 3.26-3.35 (m overlapping with water, 5H); 3.52 (m, 1H); 3.90 (m, 1H); 4.25 (m, 2H); 7.14 (d, 1H); 12.15 (s, 1H); 12.40 (s, 1H). 447, 449 Example 166 337 Trans(±)2-[4-{[(3,4-dichloro-5- 1.89 (m, 1H), 2.14 (m, 1H), 2.17 516 Example 167 methyl-1H-pyrrol-2- (s, 3H), 3.24-3.70 (m, 11H [under yl)carbonyl]amino}-3- H₂O peak]), 3.74 (dd, 1H), 3.90 (morpholin-4- (dd, 1H), 4.51 (m, 1H),_7.33 (d, ylcarbonyl)piperidin-1-yl]-1,3- 1H), 7.74 (s, 1H), 12.09 (s, 1H), thiazole-5-carboxylic acid 12.64 (s, 1H) 338 Cis(±)2-[4-{[(3,4-dichloro-5- 1.79 (dq, 1H), 1.89 (m, 1H), 2.15 516 Example 168 methyl-1H-pyrrol-2- (s, 3H), 3.21-3.42 (m, 6H), 3.49- yl)carbonyl]amino}-3- 3.72 (m, 5H), 3.95 (m, 1H), 4.02 (morpholin-4- (m, 1H), 4.40 (m, 1H), 7.17 (d, ylcarbonyl)piperidin-1-yl]-1,3- 1H), 7.78 (s, 1H), 12.02 (s, 1H), thiazole-5-carboxylic acid 12.69 (s, 1H) 339 Cis(±)-2-[4-{[(3,4-dichloro-5- 1.51 (dq, 1H), 1.98 (m, 1H), 2.18 546 Example 169 methyl-1H-pyrrol-2- (s, 3H), 3.18 (m, 2H), 3.23-3.56 yl)carbonyl]amino}-3-(2- (m, 10H [under H₂O peak]), 3.77 morpholin-4-yl-2- (m, 1H), 4.04 (m, 2H), 4.32 (q, oxoethoxy)piperidin-1-yl]-1,3- 2H), 7.36 (s, 1H), 8.26 (broad s, thiazole-5-carboxylic acid 2H) 340 2-(4-{[(3,4-dichloro-5-methyl- 1H-pyrrol-2- yl)carbonyl]amino}-3- {[(ethylamino)carbonyl]oxy} piperidin-1-yl)-1,3-thiazole-5- carboxylic acid

MS (ES) MH⁺: 490, 492 for C₁₈H₂₁Cl₂N₅O₅S; NMR: 0.96 (t, 3H), 1.82 (m, 2H), 2.17 (s, 3H), 2.96 (m, 2H), 3.19-3.40 (m, 2H) [under H₂O peak]), 3.47 (d, 1H), 3.95 (m, 1H), 4.08 (m, 1H), 4.33 (m, 1H), 4.83 (m, 1H), 6.84 (broad s, 1H), 7.14 (d, 1H), 7.21 (t, 1H), 7.46 (s, 1H) 490 Example 172 341 2-(3- NMR: 1.22 (s, 1H), 1.84 (m, 2H), 502 Example 173 {[(allylamino)carbonyl]oxy}-4- 2.17 (s, 3H), 3.52 (m, 1H), 3.57, {[(3,4-dichloro-5-methyl-1H- (m, 1H), 4.03 (m, 1H), 4.14 (m, pyrrol-2- 1H), 4.36 (m, 1H), 4.78-4.91 (m, yl)carbonyl]amino}piperidin-1- 2H), 4.99 (dd, 1H), 5.07 (dd, 1H), yl)-1,3-thiazole-5-carboxylic 5.52 (broad s, 1H), 5.73 (m 1H), acid 7.00 (d, 1H), 7.10 (broad s, 1H), 7.44 (t, 1H), 7.62 (s, 1H) 342 Cis(±)-4-(4-{[(4-chloro-5- 1.56-1.72 (m, 2H) 2.08-2.20 393 Example 177 methyl-1H-pyrrol-2- (m, 3H) 3.24 (s, 3H) 3.55 (s, 2 yl)carbonyl]amino}-3- H) 3.71-3.86 (m, 2H) 4.16 (s, 2 methoxypiperidin-1- H) 6.88 (d, 1H) 7.44 (s, 1H) yl)pyridine-2-carboxylic acid 7.68 (s, 1H) 7.97 (d, 1H) 11.69 (s, 1H) 343 Cis(±)-4-(aminocarbonyl)-2-(4- 1.74 (s, 2H) 2.19 (s, 3H) 3.38 (s, 476 Example 242 {[(3,4-dichloro-5-methyl-1H- 3H) 3.55 (s, 2H) 4.01 (s, 1H) pyrrol-2-yl)carbonyl]amino}-3- 4.25 (s, 3H) 4.49 (s, 1H) 7.16 (d, methoxypiperidin-1-yl)-1,3- 1H) 8.93 (s, 2H) 12.16 (s, 1 H thiazole-5-carboxylic acid 344 4-((3S,4R)-4-{[(3,4-dichloro-5- 1.81-1.95 (m, 2H) 2.14-2.21 415 Example 174 methyl-1H-pyrrol-2- (m, 3H) 3.73 (s, 2H) 4.26 (t, 2 yl)carbonyl]amino}-3- H) 4.62 (s, 1H) 4.93 (s, 1H) 7.22 fluoropiperidin-1-yl)pyridine- (s, 1H) 7.36 (s, 1H) 7.49 (s, 1H) 2-carboxylic acid 7.69 (s, 1H) 8.04 (d, 1H) 12.30 (s, 1H) 345 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1- yl)isonicotinic acid

1.80 (m, 2H) 2.13-2.26 (s, 3H) 4.14 (dd, 1H) 4.27 (s, 1H) 4.41 (s, 2H) 4.72 (s, 1H) 4.84-5.00 (d, 1H) 7.02 (d, 1H) 7.17-7.32 (m, 1H) 7.66-7.78 (m, 1H) 8.24 (d, 1H) 12.11 (s, 1H) 415 Example 179 346 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.85 (s, 2H) 2.19 (s, 3H) 3.28 (s, 465 Example 180 methyl-1H-pyrrol-2- 3H) 3.50-3.64 (dd, 1H) 3.98 (s, yl)carbonyl]amino}-3- 1H) 4.32 (s, 2H) 4.57 (s, 2H) fluoropiperidin-1-yl)-4- 4.88-5.04 (d, 1H) 7.29 (d, 1H) (methoxymethyl)-1,3-thiazole- 12.12 (s, 1H) 12.79 (s, 1H) 5-carboxylic acid 347 4-((3S,4R)-4-{[(3,4-dichloro-5- 2.00 (s, 2H) 2.21 (s, 3H) 3.33 (s, 465 Example 181 methyl-1H-pyrrol-2- 1H) 3.78 (d, 1H) 4.08 (s, 2H) yl)carbonyl]amino}-3- 4.32-4.42 (m, 1H) 4.95-5.11 (d, fluoropiperidin-1-yl)quinoline- 1H) 7.34 (d, 1H) 7.60 (s, 2H) 2-carboxylic acid 7.69 (t, 1H) 7.84 (t, 1H) 8.08- 8.22 (m, 2H) 12.15 (s, 1H) 348 Cis(±)-2-(4-{[(4-chloro-5- 1.57 (d, 1H) 1.86 (d, 1H) 2.14 393 Example 182 methyl-1H-pyrrol-2- (s, 3H) 3.04-3.18 (m, 2H) 3.19- yl)carbonyl]amino}-3- 3.25 (s, 3H) 3.49 (s, 1H) 4.19 methoxypiperidin-1- (s, 1H) 4.21 (d, 1H) 4.55 (d, 1 yl)isonicotinic acid H) 6.89 (d, 1H) 6.96 (d, 1H) 7.23 (s, 1H) 7.64 (d, 1H) 8.22 (d, 1H) 11.62 (s, 1H) 13.39 (s, 1H) 349 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.68 (s, 2H) 2.12 (s, 3H) 3.21 (s, 477 Example 183 methyl-1H-pyrrol-2- 3H) 3.33 (m, 5H) 3.48 (s, 1H) yl)carbonyl]amino}-3- 3.85 (s, 1H) 4.19 (s, 2H) 4.49 (s, methoxypiperidin-1-yl)-4- 2H) 7.08 (s, 1H) 12.09 (s, 1H) (methoxymethyl)-1,3-thiazole- 5-carboxylic acid 350 2-((3R,4S)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- (methoxymethyl)-1,3-thiazole- 5-carboxylic acid

1.68 (s, 2H) 2.12 (s, 3H) 3.21 (s, 3H) 3.25 (m, 2H) 3.30 (s, 3H) 3.48 (s, 1H) 3.84 (s, 1H) 4.19 (s, 2H) 4.49 (s, 2H) 7.09 (d, 1H) 12.09 (s, 1H) 477 Example 184 351 Cis(±)-4-(4-{[(3,4-dichloro-5- 1.68 (s, 1H) 1.77 (s, 1H) 2.18 (s, 471 Example 185 methyl-1H-pyrrol-2- 3H) 3.21 (s, 2H) 3.31 (s, 3H) yl)carbonyl]amino}-3- 3.55 (s, 1H) 4.02 (s, 1H) 4.28 (s, methoxypiperidin-1- 1H) 4.41 (s, 1H) 7.13 (s, 1H) yl)pyridine-2,6-dicarboxylic acid 7.61 (s, 2H) 12.13 (s, 1H) 352 4-((3S,4R)-4-{[(3,4-dichloro-5- 1.71-1.86 (m, 2H) 2.22 (s, 3H) 486 Example 187 methyl-1H-pyrrol-2- 2.93-3.04 (m, 3H) 3.04-3.15 yl)carbonyl]amino}-3- (m, 3H) 3.80-3.96 (m, 1H) 4.08 fluoropiperidin-1-yl)-6- (s, 1H) 4.28-4.43 (m, 2H) 4.77 [(dimethylamino)carbonyl] (s, 1H) 4.94 (s, 1H) 6.87 (d, 1H) pyridine-2-carboxylic acid 7.10 (d, 1H) 7.58 (d, 1H) 9.33 (s, 2H) 353 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.75 (s, 2H) 2.18 (s, 3H) 3.33 (s, 477 Example 175 methyl-1H-pyrrol-2- 2H) 3.37 (s, 3H) 3.55 (s, 1H) yl)carbonyl]amino}-3- 3.92 (s, 1H) 4.26 (s, 2H) 7.15 (d, methoxypiperidin-1-yl)-1,3- 1H) 12.14 (s, 1H) thiazole-4,5-dicarboxylic acid 354 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.85 (s, 2H) 2.19 (s, 3H) 3.33 (s, 465 Example 176 methyl-1H-pyrrol-2- 1H) 3.60 (s, 1H) 3.99 (s, 1H) yl)carbonyl]amino}-3- 4.31 (s, 2H) 4.88-5.04 (s, 1H) fluoropiperidin-1-yl)-1,3- 7.28 (s, 1H) 12.09 (s, 1H) thiazole-4,5-dicarboxylic acid 355 Cis(±)-2-(4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- formyl-1,3-thiazole-5- carboxylic acid

1.75 (s, 2H) 2.18 (s, 3H) 3.17 (s, 1H) 3.36 (s, 3H) 3.56 (s, 1H) 4.01 (s, 2H) 4.25 (s, 2H) 7.15 (d, 1H) 10.35 (s, 1H) 12.15 (s, 1H) 461 Example 252 356 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.69 (s, 2H) 2.12 (s, 3H) 2.72 (s, 504 Example 203 methyl-1H-pyrrol-2- 3H) 2.82-2.88 (m, 3H) 3.22 (s, yl)carbonyl]amino}-3- 1H) 3.29 (s, 3H) 3.32 (s, 1H) methoxypiperidin-1-yl)-4- 3.48 (d, 1H) 3.81 (s, 1H) 4.21 (s, [(dimethylamino)carbonyl]- 2H) 7.09 (d, 1H) 12.03-12.13 1,3-thiazole-5-carboxylic acid (m, 1H) 12.68 (s, 1H) 357 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.75 (s, 2H) 2.18 (s, 3H) 3.12- 546 Example 204 methyl-1H-pyrrol-2- 3.22 (m, 2H) 3.35 (s, 3H) 3.53 yl)carbonyl]amino}-3- (d, 6H) 3.60 (d, 2H) 3.85 (s, 2 methoxypiperidin-1-yl)-4- H) 4.27 (s, 2H) 7.14 (d, 1H) (morpholin-4-ylcarbonyl)-1,3- 12.13 (s, 1H) 12.81 (s, 1H) thiazole-5-carboxylic acid 358 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.84 (s, 2H) 2.18 (s, 3H) 3.16 (s, 534 Example 205 methyl-1H-pyrrol-2- 2H) 3.51 (s, 2H) 3.52-3.64 (m, yl)carbonyl]amino}-3- 5H) 3.96 (s, 1H) 4.29 (s, 2H) fluoropiperidin-1-yl)-4- 4.37 (s, 1H) 4.87-5.04 (d, 1H) (morpholin-4-ylcarbonyl)-1,3- 7.26 (d, 1H) 12.07 (s, 2H) thiazole-5-carboxylic acid 359 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.79 (s, 2H) 2.19 (s, 3H) 3.38 (s, 506 Example 206 methyl-1H-pyrrol-2- 3H) 3.56 (s, 2H) 3.64 (s, 1H) yl)carbonyl]amino}-3- 3.75 (s, 3H) 4.03 (s, 1H) 4.25 (s, methoxypiperidin-1-yl)-4- 2H) 7.16 (d, 1H) 12.16 (s, 1H) [(methoxyamino)carbonyl]-1,3- thiazole-5-carboxylic acid trifluoroacetate 360 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-4- [(methoxyamino)carbonyl]-1,3- thiazole-5-carboxylic acid

1.83-1.92 (m, 2H) 2.19 (s, 3H) 3.50-3.63 (dd, 1H) 3.76 (s, 3H) 4.11 (s, 1H) 4.30 (s, 1H) 4.42 (s, 2H) 4.90-5.07 (s, 1H) 7.29 (d, 1+nlH) 12.11 (s, 1H) 12.39 (s, 1H) 494 Example 207 361 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.51 (s, 3H) 1.57 (s, 1H) 1.75 (s, 544 Example 208 methyl-1H-pyrrol-2- 2H) 2.18 (s, 3H) 3.07-3.17 (m, yl)carbonyl]amino}-3- 2H) 3.35 (s, 3H) 3.54 (d, 2H) methoxypiperidin-1-yl)-4- 3.87 (s, 1H) 4.27 9s, 2H) 7.16 (d, (piperidin-1-ylcarbonyl)-1,3- 1H) 12.16 (s, 1H) 12.76 (s, 1H) thiazole-5-carboxylic acid 362 4-(aminocarbonyl)-2-((3S,4R)- 1.74 (d, 2H) 2.19 (s, 3H) 3.32 (s, 476 Example 243 4-{[(3,4-dichloro-5-methyl-1H- 2H) 3.38 (s, 3H) 3.55 (s, 1H) pyrrol-2-yl)carbonyl]amino}-3- 4.25 (s, 2H) 4.49 (s, 1H) 7.17 (d, methoxypiperidin-1-yl)-1,3- 1H) 8.87 (s, 1H) 12.17 (s, 1H) thiazole-5-carboxylic acid 363 4-(aminocarbonyl)-2-((3S,4R)- 1.84 (s, 2H) 2.19 (s, 3H) 3.19 (s, 464 Example 244 4-{[(3,4-dichloro-5-methyl-1H- 1H) 3.95 (s, 2H) 4.24 (s, 2H) pyrrol-2-yl)carbonyl]amino}-3- 4.86-5.02 (s, 1H) 7.28 (s, 1H) fluoropiperidin-1-yl)-1,3- 12.12 (s, 1H) thiazole-5-carboxylic acid 364 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.60-1.73 (m, 2H) 2.12 (s, 3H) 520 Example 212 methyl-1H-pyrrol-2- 3.14-3.25 (m, 2H) 3.30 (s, 3H) yl)carbonyl]amino}-3- 3.41 (t, 2H) 3.86 (s, 2H) 4.19 (s, methoxypiperidin-1-yl)-5-{[(2- 2H) 7.09 (d, 1H) 9.66 (t, 1H) hydroxyethyl)amino]carbonyl}- 12.09 (s, 1H) 1,3-thiazole-4-carboxylic acid trifluoroacetate (salt) 365 Cis(±)-2-(4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-{[(2- hydroxyethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylic acid

1.69 (s, 2H) 2.12 (s, 3H) 3.25 (s, 2H) 3.31 (s, 3H) 3.43-3.53 (m, 2H) 4.03 (s, 1H) 4.23 (s, 2H) 4.80 (s, 1H) 7.07-7.22 (m, 1H) 9.23 (s, 1H) 12.09 (s, 1H) 520 Example 212 366 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.84 (s, 2H) 2.18 (s, 3H) 2.76 (s, 478 Example 211 methyl-1H-pyrrol-2- 3H) 3.31 (s, 1H) 3.40 (s, 1H) yl)carbonyl]amino}-3- 3.61 (s, 1H) 3.98 (s, 1H) 4.29 (s, fluoropiperidin-1-yl)-5- 1H) 4.87-5.03 (s, 1H) 7.26 (s, 1 [(methylamino)carbonyl]-1,3- H) 9.43 (s, 1H) 12.11 (s, 1H) thiazole-4-carboxylic acid 367 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.87 (s, 2H) 2.19 (s, 3H) 2.87 (s, 478 Example 211 methyl-1H-pyrrol-2- 3H) 3.53 (s, 1H) 4.13 (s, 1H) yl)carbonyl]amino}-3- 4.30 (s, 1H) 4.43 (s, 2H) 4.91- fluoropiperidin-1-yl)-4- 5.07 (d, 1H) 7.31 (s, 1H) 9.40 (s, [(methylamino)carbonyl]-1,3- 1H) 12.11 (s, 1H) thiazole-5-carboxylic acid 368 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.76 (s, 2H) 2.19 (s, 3H) 2.91 (q, 476 Example 355 methyl-1H-pyrrol-2- 1H) 3.03 (d, 1H) 3.35-3.38 (m, yl)carbonyl]amino}-3- 3H) 3.53 (s, 1H) 3.93 (s, 1H) methoxypiperidin-1-yl)-4- 4.03 (d, 1H) 4.23 (s, 1H) 7.20 [(hydroxyimino)methyl]-1,3- (d, 1H) 7.54 (s, 1H) 7.83 (s, 1H) thiazole-5-carboxylic acid 8.76 (s, 1H) 369 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.70-1.82 (m, 2H) 2.19 (s, 3H) 490 Example 214 methyl-1H-pyrrol-2- 3.32 (s, 3H) 3.38 (s, 3H) 3.41 (s, yl)carbonyl]amino}-3- 1H) 3.56 (s, 1H) 4.09 (s, 1H) methoxypiperidin-1-yl)-4- 4.29 (d, 2H) 4.46 (s, 1H) 7.17 [(methylamino)carbonyl]-1,3- (d, 1H) 9.38 (s, 1H) 12.17 (s, 1 thiazole-5-carboxylic acid H) 370 Cis(±)-2-(4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-[(E)- (methoxyimino)methyl]-1,3- thiazole-5-carboxylic acid

1.69 (s, 2H) 2.12 (s, 3H) 3.31 (s, 3H) 3.49 (s, 2H) 3.84 (s, 3H) 3.96 (s, 2H) 4.21 (s, 2H) 7.10 (d, 1H) 8.62 (s, 1H) 12.10 (s, 1H) 490 Example 251 371 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.61-1.71 (m, 2H) 2.10-2.14 532 Example 246 methyl-1H-pyrrol-2- (m, 3H) 2.68 (s, 3H) 3.29 (s, 3 yl)carbonyl]amino}-3- H) 3.47 (d, 1H) 3.58 (s, 4H) methoxypiperidin-1-yl)-4- 3.67-3.80 (m, 2H) 3.84 (d, 2H) (morpholin-4-ylmethyl)-1,3- 4.19 (t, 2H) 7.10 (d, 1H) 12.12 thiazole-5-carboxylic acid (s, 1H) 372 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.60-1.74 (m, 2H) 2.12 (s, 3H) 483 Example 253 methyl-1H-pyrrol-2- 3.27 (s, 1H) 3.30 (s, 3H) 3.34 (s, yl)carbonyl]amino}-3- 1H) 3.49 (s, 1H) 3.87 (s, 1H) methoxypiperidin-1-yl)-4- 4.21 (s, 2H) 7.10 (d, 1H) 7.27 (s, (difluoromethyl)-1,3-thiazole- 1H) 12.10 (s, 1H) 5-carboxylic acid 373 Cis(±)-4-[(tert- 1.26 (s, 9H) 1.72 (s, 2H) 2.18 (s, 518 Example 247 butylamino)methyl]-2-(4- 3H) 3.32 (m, 3H) 3.36 (s, 3H) {[(3,4-dichloro-5-methyl-1H- 3.52 (s, 1H) 3.95 (s, 2H) 4.18 (s, pyrrol-2-yl)carbonyl]amino}-3- 2H) 7.15 (d, 1H) 12.18 (s, 1H) methoxypiperidin-1-yl)-1,3- thiazole-5-carboxylic acid 374 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.11-1.20 (m, 3H) 1.76 (s, 2H) 534 Example 216 methyl-1H-pyrrol-2- 2.19 (s, 3H) 3.38 (s, 3H) 3.48 (d, yl)carbonyl]amino}-3- 3H) 3.57 (s, 1H) 4.04 (s, 1H) methoxypiperidin-1-yl)-4-{[(2- 4.27 (s, 2H) 4.91 (s, 2H) 7.17 (d, hydroxy-1- 1H) 8.83 (s, 1H) 12.16 (s, 1H) methylethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylic acid 375 Cis(±)-2-(4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-{[(2- methoxyethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylic acid

1.79 (s, 3H) 2.19 (s, 3H) 3.23- 3.28 (m, 3H) 3.38 (s, 3H) 3.42 (s, 2H) 3.46-3.52 (m, 2H) 3.57 (s, 1H) 4.30 (d, 2H) 7.17 (d, J = 8.48 Hz, 1H) 9.38 (s, 1H) 12.16 (s, 1H) 534 Example 215 376 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.06 (d, 3H) 1.69-1.79 (m, 3H) 534 Example 217 methyl-1H-pyrrol-2- 2.18 (s, 3H) 3.37 (s, 3H) 3.54 (s, yl)carbonyl]amino}-3- 2H) 3.71 (s, 1H) 3.94 (s, 1H) methoxypiperidin-1-yl)-5-{[(2- 4.25 (s, 3H) 4.79 (s, 1H) 6.55 (s, hydroxypropyl)amino]carbonyl}- 1H) 7.17 (s, 1H) 9.78 (s, 1H) 1,3-thiazole-4-carboxylic acid 12.16 (s, 1H) 377 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.06 (dd, 3H) 1.75 (s, 2H) 2.19 534 Example 217 methyl-1H-pyrrol-2- (s, 3H) 3.24 (s, 2H) 3.38 (s, 3H) yl)carbonyl]amino}-3- 3.43 (s, 1H) 3.56 (s, 1H) 3.83 (s, methoxypiperidin-1-yl)-4-{[(2- 1H) 4.05 (s, 1H) 4.26 (s, 2H) hydroxypropyl)amino]carbonyl}- 4.90 (s, 1H) 7.17 (d, 1H) 9.21 (s, 1,3-thiazole-5-carboxylic acid 1H) 12.16 (s, 1H) 378 Cis(±)-2-(4-{[(3,4-dichloro-5- 1.69 (s, 6H) 2.18 (s, 3H) 3.34 (s, 530 Example 248 methyl-1H-pyrrol-2- 3H) 3.40 (m, 3H) 3.54 (s, 5H) yl)carbonyl]amino}-3- 4.24 (s, 4H) 7.14 (d, 1H) 12.16 methoxypiperidin-1-yl)-4- (s, 1H) (piperidin-1-ylmethyl)-1,3- thiazole-5-carboxylic acid 379 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.75 (s, 2H) 2.19 (s, 3H) 3.17 433 Example 192 methyl-1H-pyrrol-2- (d, 1H) 3.27 (s, 1H) 3.36 (s, 3H) yl)carbonyl]amino}-3- 3.54 (s, 1H) 3.85 (s, 1H) 4.21 (d, methoxypiperidin-1-yl)-1,3- 2H) 7.16 (d, 1H) 7.58 (s, 1H) thiazole-4-carboxylic acid 12.16 (s, 1H) 12.57 (s, 1H) 380 2-((3S,4R)-4-{[(3,4-dichloro-5- 1.73 (d, 3H) 2.07 (s, 1H) 2.18 (s, 532 Example 249 methyl-1H-pyrrol-2- 3H) 2.95 (s, 2H) 3.26 (s, 2H) yl)carbonyl]amino}-3- 3.36 (s, 3H) 3.53 (s, 1H) 3.85 (s, methoxypiperidin-1-yl)-4-[(3- 1H) 4.15 (s, 4H) 4.35 (s, 1H) hydroxypyrrolidin-1- 5.20 (s, 1H) 7.16 (d, 1H) 12.16 yl)methyl]-1,3-thiazole-5- (s, 1H) carboxylic acid 381 4-{[(1- 1.25 (s, 2H) 1.48 (s, 2H) 1.75 (s, 560 Example 402 carboxycyclopropyl)amino] 2H) 2.19 (s, 3H) 3.39 (s, 4H) carbonyl}-2-((3S,4R)-4-{[(3,4- 3.56 (s, 2H) 4.26 (s, 2H) 4.42 (s, dichloro-5-methyl-1H-pyrrol- 1H) 7.15 (s, 1H) 9.80 (s, 1H) 2-yl)carbonyl]amino}-3- 12.15 (s, 1H) 12.78 (s, 1H) methoxypiperidin-1-yl)-1,3- 16.05 (s, 1H) thiazole-5-carboxylic acid

Example 382 Cis(±)-5-(aminocarbonyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-4-carboxylic acid

A solution of 55 mg (23 mmol) of Cis(±)-3,4-dichloro-N-[3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 50), 55 mg (0.23 mmol) of ethyl 5-(aminocarbonyl)-2-chloro-1,3-thiazole-4-carboxylate (Intermediate 220) and 33 mg (0.23 mmol) K₂CO₃ in 3 ml NMP was heated at 150° C. for 1 h in a microwave reactor. Water (0.1 ml) was added and the mixture was heated at 150° C. for another hour. The solution was diluted with water and acidified with 1N HCl before being extracted 2 times with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO₄) and concentrated to give a solid that was triturated with MeOH to give 41 mg of a white solid. MS (ES) MH⁺: 479 for C₁₇H₁₉Cl₂N₅O₅S; NMR: 1.75 (m, 2H), 2.2 (s, 3H), 3.3 (s), 3.5 (s, 1H), 3.9 (m, 1H), 4.2 (m, 2H), 7.15 (d, 1H), 7.8 (s, 1H), 8.9 (s, 1H), 12.2 (s, 1H).

Example 383 Cis(±)-5-(aminocarbonyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinic acid

A mixture of 85 mg (0.17 mmol) of Cis(±)-ethyl 5-(aminocarbonyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 198) and 86 mg (0.50 mmol) Ba(OH)₂ in 3 ml MeOH and 2 ml water was heated at 120° C. for 1 h. The mixture was acidified to about pH=4 with 1N HCl and extracted 4 times with EtOAc. The EtOAc was concentrated and the residue was purified by reverse phase HPLC (20-40% CH₃CN gradient in water with 0.1% TFA) to afford 8 mg of product as a white solid. MS (ES) MH⁺: 470 for C₁₉H₂₁Cl₂N₅O₅; NMR: 1.5-1.8, (m, 3H), 2.2 (s, 3H), 3.0-3.2 (m, 2H), 3.3 (s, 3H), 3.5 (m, 2H), 4.2-4.5 (m, 2H), 4.9 (d, 1H), 6.9 (s, 1H), 7.1-7.3 (m, 2H), 7.8 (s, 1H), 8.4 (s, 1H), 12.1 (s, 1H), 13.1 (s, 1H).

Examples 384-385

The following Examples were synthesized by an analogous method to Example 383 from the starting materials (SM) given in the table below.

Ex Compound NMR m/z SM 384 2-((3S,4R)-4-{[(3,5-dichloro-4- NMR: 1.8 (m, MS (ES) MH⁺: 577 Intermediate 138 methyl-1H-pyrrol-2- 2H), 1.9 (s, 3H), for yl)carbonyl]amino}-3- 3.5-4.0 (m, 8H), C₂₂H₂₇Cl₂FN₆O₅S fluoropiperidin-1-yl)-4-{[(2- 4.0-4.4 (m, 3H), morpholin-4- 5.0 (d, 1H), 7.4 ylethyl)amino]carbonyl}-1,3- (d, 1H), 9.5 (s, thiazole-5-carboxylic acid 1H), 12.6 (s, 1H). 385 4-(aminocarbonyl)-2-((3S,4R)- 4-{[(3,5-dichloro-4-methyl- 1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylic acid

NMR: 1.8 (m, 2H), 1.9 (s, 3H), 3.5-4.0 (m, 8H), 4.0-4.4 (m, 3H), 5.0 (d, 1H), 7.4 (d, 1H), 9.5 (s, 1H, 12.6 (s, 1H.) MS (ES) MH⁺: 464 for C₁₆H₁₆Cl₂FN₅ O₄S Example 202

Example 386 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(methylamino)carbonyl]-1,3-thiazole-5-carboxylic acid

To a suspension/solution of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(methylamino)carbonyl]-1,3-thiazole-5-carboxylate (0.078 g, 0.15 mmol, Example 218) in methanol (2 mL) was added barium hydroxide (0.052 g, 0.30 mmol) and water (0.5 mL). After stirring several hours the reaction was complete. The reaction was acidified with 1N HCl and then concentrated to remove methanol. The residue was extracted with EtOAc (×3), dried with MgSO₄ and concentrated to a white solid (0.059 g). MS (ES) M+H⁺: 490 for C₁₈H₂₁Cl₂N₅O₅S; NMR: 1.76 (s, 2 H) 2.18 (s, 3 H) 2.86 (s, 3 H) 3.38 (s, 3 H) 3.56 (s, 2 H) 4.02 (s, 1 H) 4.27 (s, 2 H) 4.40 (s, 1 H) 7.15 (s, 1 H) 9.38 (s, 1 H) 12.15 (s, 1 H).

Examples 387-412

The following Examples were prepared by the procedure described in Example 386 from the starting materials (SM) indicated.

Ex Compound Data SM 387 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 534 for Example 219 methyl-1H-pyrrol-2- C₂₀H₂₅Cl₂N₅O₆S; yl)carbonyl]amino}-3- NMR: 1.72 (s, 2H) 2.18 (s, 3H) methoxypiperidin-1-yl)-4-{[(2- 3.24 (s, 3H) 3.36 (s, 3H) 3.51 (s, methoxyethyl)amino]carbonyl}- 2H) 3.84 (s, 2H) 4.15 (s, 2H) 1,3-thiazole-5-carboxylic acid 7.15 (s, 1H) 12.16 (s, 1H) 13.18 (s, 1H) 388 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 534 for Example 220 methyl-1H-pyrrol-2- C₂₀H₂₅Cl₂N₅O₆S; yl)carbonyl]amino}-3- NMR: 1.19 (s, 3H) 1.77 (s, 2H) methoxypiperidin-1-yl)-4- 2.19 (s, 3H) 3.38 (s, 3H) 3.47 (s, ({[(1S)-2-hydroxy-1- 3H) 3.58 (s, 1H) 4.04 (s, 1H) methylethyl]amino}carbonyl)- 4.29 (s, 2H) 4.91 (s, 1H) 7.18 (s, 1,3-thiazole-5-carboxylic acid 1H) 8.79-8.94 (m, 1H) 12.16 (s, 1H) 389 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 534 for Example 221 methyl-1H-pyrrol-2- C₂₀H₂₅Cl₂N₅O₆S yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1R)-2-hydroxy-1- methylethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylic acid 390 Cis(±)-2-(4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-{[(2,2- difluoroethyl)amino]carbonyl}- 1,3-thiazole-5-carboxylic acid

MS (ES) MH⁺: 540 for C₁₉H₂₁Cl₂F₂N₅O₅S; NMR: 1.76 (s, 2H) 2.19 (s, 3H) 3.38 (s, 3H) 3.44 (s, 1H) 3.57 (s, 2H) 3.73 (s, 3H) 4.10 (s, 1H) 4.27 (d, 2H) 4.43 (s, 1H) 7.17 (d, 1H) 9.60 (s, 1H) 12.16 (s, 1+nlH) 15.77 (s, 1H) Example 222 391 Cis(±)-2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 543 for Example 223 methyl-1H-pyrrol-2- C₂₀H₂₀Cl₂N₆O₆S; yl)carbonyl]amino}-3- NMR: 1.74 (s, 2H) 2.19 (s, 3H) methoxypiperidin-1-yl)-4- 3.22 (s, 2H) 3.38 (s, 3H) 3.52 (s, [(isoxazol-3-ylamino)carbonyl]- 1H) 3.88 (s, 1H) 4.24 (s, 2H) 1,3-thiazole-5-carboxylic acid 6.99 (d, 1H) 7.16 (s, 1H) 8.75 (s, 1H) 12.16 (s, 1H) 392 Cis(±)-2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 546 for Example 224 methyl-1H-pyrrol-2- C₂₁H₂₅Cl₂N₅O₆S; yl)carbonyl]amino}-3- NMR: 1.76 (s, 3H) 1.94-2.08 methoxypiperidin-1-yl)-4-{[(3R)- (m, 1H) 2.19 (s, 3H) 3.38 (s, 3 tetrahydrofuran-3- H) 3.44 (s, 1H) 3.56 (s, 1H) ylamino]carbonyl}-1,3-thiazole- 3.63-3.76 (m, 2H) 3.81-3.92 5-carboxylic acid (m, 2H) 4.12 (s, 1H) 4.26 (s, 1 H) 4.51 (s, 1H) 7.16 (d, 1H) 9.17 (d, 1H) 12.15 (s, 1H) 15.97 (s, 1H) 393 Cis(±)-2-(4-{[(3,4-dichloro-5- MS (ES) MH⁺: 534 for Example 225 methyl-1H-pyrrol-2- C₂₀H₂₂Cl₂FN₅O₅S; yl)carbonyl]amino}-3- NMR: 1.23 (dd, 2H) 1.75 (s, 2 methoxypiperidin-1-yl)-4- H) 2.19 (s, 3H) 2.87 (s, 1H) ({[(1R,2S)-2- 3.37 (d, 3H) 3.42 (s, 1H) 3.56 fluorocyclopropyl]amino}carbon- (s, 2H) 4.10 (s, 1H) 4.26 (s, 3H) yl)-1,3-thiazole-5-carboxylic acid 4.45 (s, 1H) 4.73 (d, 1H) 4.96 (s, 1H) 7.16 (d, 1H) 9.29 (dd, 1 H) 12.15 (s, 2H) 16.02 (d, 1H) 394 4-(azidomethyl)-2-((3S,4R)-4- MS (ES) MH⁺: 488 for Example 254 {[(3,4-dichloro-5-methyl-1H- C₁₇H₁₉Cl₂N₇O₄S; pyrrol-2-yl)carbonyl]amino}-3- NMR: 1.76 (s, 2H) 2.18 (s, 3H) methoxypiperidin-1-yl)-1,3- 3.37 (s, 5H) 3.56 (s, 1H) 3.92 (s, thiazole-5-carboxylic acid 1H) 4.28 (s, 2H) 4.54 (d, 2H) 7.18 (s, 1H) 12.16 (s, 1H) 12.97 (s, 1H) 395 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1S)-2-methoxy-1- methylethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylic acid

MS (ES) MH⁺: 548 for C₂₁H₂₇Cl₂N₅O₆S; NMR: 1.18 (d, 3H) 1.76 (s, 2H) 2.18 (s, 3H) 3.24 (s, 3H) 3.38 (s, 3H) 3.49 (s, 2H) 3.57 (s, 1H) 4.06 (s, 1H) 4.26 (s, 2H) 7.15 (s, 1H) 8.95 (s, 1H) 12.16 (s, 1H) 16.33 (s, 1H) Example 226 396 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 514 for Example 227 methyl-1H-pyrrol-2- C₂₀H₂₁Cl₂N₅O₅S; yl)carbonyl]amino}-3- NMR: 1.76 (s, 2H) 2.19 (s, 3H) methoxypiperidin-1-yl)-4-[(prop- 3.26 (s, 2H) 3.38 (s, 3H) 3.57 (s, 2-yn-1-ylamino)carbonyl]-1,3- 2H) 4.10 (d, 2H) 4.27 (s, 2H) thiazole-5-carboxylic acid 7.17 (d, 1H) 9.78 (s, 1H) 12.16 (s, 1H) 15.96 (s, 1H) 397 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 548 for Example 228 methyl-1H-pyrrol-2- C₂₁H₂₇Cl₂N₅O₆S; yl)carbonyl]amino}-3- NMR: 1.29 (s, 6H) 1.73 (s, 2H) methoxypiperidin-1-yl)-4-{[(2- 2.17 (s, 3H) 3.37 (m, 6H) 3.46 hydroxy-1,1- (s, 2H) 3.54 (s, 1H) 3.91 (s, 1H) dimethylethyl)amino]carbonyl}- 4.23 (s, 2H) 7.16 (s, 1H) 12.19 1,3-thiazole-5-carboxylic acid (s, 1H) 398 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 546 for Example 224 methyl-1H-pyrrol-2- C₂₁H₂₅Cl₂N₅O₆S; yl)carbonyl]amino}-3- NMR: 1.23 (s, 1H) 1.76 (s, 2H) methoxypiperidin-1-yl)-4-{[(3R)- 2.00 (d, 1H) 2.19 (s, 3H) 3.38 tetrahydrofuran-3- (s, 6H) 3.43 (s, 1H) 3.56 (s, 1H) ylamino]carbonyl}-1,3-thiazole- 3.64-3.77 (m, 2H) 3.79-3.94 5-carboxylic acid (m, 2H) 4.26 (s, 1H) 4.51 (s, 1 H) 7.16 (d, 1H) 9.17 (s, 1H) 12.16 (s, 1H) 15.98 (s, 1H) 399 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 534 for Example 229 methyl-1H-pyrrol-2- C₂₀H₂₂Cl₂FN₅O₅S; yl)carbonyl]amino}-3- NMR: 1.21 (d, 1H) 1.40 (s, 1H) methoxypiperidin-1-yl)-4- 1.76 (s, 2H) 2.19 (s, 3H) 2.85 (s, ({[(1R,2S)-2- 1H) 3.38 (s, 3H) 3.43 (s, 3H) fluorocyclopropyl]amino}carbon- 3.56 (s, 1H) 4.26 (s, 1H) 4.74- yl)-1,3-thiazole-5-carboxylic acid 4.97 (d, 1H) 7.17 (d, 1H) 9.27 (d, 1H) 12.16 (s, 2H) 16.01 (s, 2 H) 400 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1- yl)isonicotinic acid

MS (ES) MH⁺: 427 for C₁₈H₂₀Cl₂N₄O₄ NMR: 1.72 (s, 2H) 2.18 (s, 3H) 3.13 (d, 2H) 3.30 (s, 3H) 3.49 (s, 1H) 4.17-4.31 (m, 2H) 4.68 (d, 1H) 6.97 (d, 1H) 7.15 (d, 1+nlH) 7.23 (s, 1H) 8.22 (d, 1H) 12.16 (s, 1H) 13.39 (s, 1H) Example 193 401 4-[(cyclopropylamino)carbonyl]- MS (ES) MH⁺: 516 for Example 231 2-((3S,4R)-4-{[(3,4-dichloro-5- C₂₀H₂₃Cl₂N₅O₅S; methyl-1H-pyrrol-2- NMR: 0.77 (d, 2H) 0.80 (s, 2H) yl)carbonyl]amino}-3- 1.76 (s, 2H) 2.19 (s, 3H) 2.86- methoxypiperidin-1-yl)-1,3- 2.99 (m, 1H) 3.30 (s, 1H) 3.37 thiazole-5-carboxylic acid (s, 3H) 3.56 (s, 1H) 4.16 (s, 1H) 4.26 (d, 2H) 4.41 (s, 1H) 7.16 (d, 1H) 9.22 (d, 1H) 12.15 (s, 1H) 402 1-({[2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 574 for Example 230 dichloro-5-methyl-1H-pyrrol-2- C₂₂H₂₅Cl₂N₅O₇S; yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-5- (methoxycarbonyl)-1,3-thiazol-4- yl]carbonyl}amino)cyclopropane carboxylic acid 403 4-{[(1-carboxy-2- MS (ES) MH⁺: 564 for Example 233 hydroxyethyl)amino]carbonyl}- C₂₀H₂₃Cl₂N₅O₈S; 2-((3S,4R)-4-{[(3,4-dichloro-5- NMR: 1.78 (s, 2H) 2.19 (s, 3H) methyl-1H-pyrrol-2- 3.39 (s, 3H) 3.47 (s, 2H) 3.59 (s, yl)carbonyl]amino}-3- 1H) 3.87 (s, 2H) 4.30 (s, 2H) methoxypiperidin-1-yl)-1,3- 4.53 (s, 1H) 7.16 (s, 1H) 9.03 (s, thiazole-5-carboxylic acid 1H) 12.16 (s, 1H) 15.97 (s, 1H) 404 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 589 for Example 234 methyl-1H-pyrrol-2- C₂₃H₃₀Cl₂N₆O₆S; yl)carbonyl]amino}-3- NMR: 1.76 (s, 2H) 2.19 (s, 3H) methoxypiperidin-1-yl)-4-{[(2- 3.14 (d, 2H) 3.39 (s, 4H) 3.57 morpholin-4- (s, 3H) 3.72 (s, 3H) 3.78 (s, 1H) ylethyl)amino]carbonyl}-1,3- 3.96 (s, 2H) 4.27 (s, 2H) 7.18 thiazole-5-carboxylic acid (d, 1H) 9.59 (s, 1H) 12.21 (s, 1H) 405 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-{[(1,3- dioxolan-2- ylmethyl)amino]carbonyl}-1,3- thiazole-5-carboxylic acid

MS (ES) MH⁺: 562 for C₂₁H₂₅Cl₂N₅O₇S; NMR: 1.77 (s, 2H) 2.19 (s, 3H) 3.39 (s, 9H) 3.44-3.52 (m, 2H) 3.58 (s, 1H) 3.79-3.87 (m, 2H) 3.89-3.97 (m, 2H) 4.27 (s, 2H) 5.05 (t, 1H) 7.17 (d, 1H) 9.39 (t, 1H) 12.16 (s, 1H) 16.20 (s, 1H) Example 235 406 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 567 for Example 237 methyl-1H-pyrrol-2- C₂₃H₂₄Cl₂N₆O₅S; yl)carbonyl]amino}-3- NMR: 1.77 (s, 2H) 2.19 (s, 3H) methoxypiperidin-1-yl)-4- 3.40 (s, 3H) 3.58 (s, 2H) 4.28 (s, {[(pyridin-2- 2H) 4.67 (s, 2H) 7.16 (s, 1H) ylmethyl)amino]carbonyl}-1,3- 7.31-7.45 (m, 2H) 7.85 (s, 1H) thiazole-5-carboxylic acid 8.56 (s, 1H) 9.97 (s, 1H) 12.17 (s, 1H) 16.14 (s, 1H) 407 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 601 for Example 236 methyl-1H-pyrrol-2- C₂₄H₃₀Cl₂N₆O₆S; yl)carbonyl]amino}-3- NMR: 1.71 (s, 1H) 1.74 (d, 3H) methoxypiperidin-1-yl)-4-({[3- 1.85-2.00 (m, 2H) 2.19 (s, 3H) (2-oxopyrrolidin-1- 2.20-2.27 (m, 2H) 3.19-3.35 yl)propyl]amino}carbonyl)-1,3- (m, 11H) 3.39 (s, 4H) 3.56 (s, 1 thiazole-5-carboxylic acid H) 4.20-4.34 (m, 1H) 7.17 (d, 1 H) 9.45 (t, 1H) 12.16 (s, 1H) 408 Cis(±)-4-[cyano(morpholin-4- MS (ES) MH⁺: 557 for Example 255 yl)methyl]-2-(4-{[(3,4-dichloro- C₂₂H₂₆Cl₂N₆O₅S; 5-methyl-1H-pyrrol-2- NMR: 1.75 (s, 2H) 2.18 (s, 3H) yl)carbonyl]amino}-3- 2.71 (s, 3H) 3.39 (s, 2H) 3.43 (s, methoxypiperidin-1-yl)-1,3- 5H) 3.59 (s, 4H) 3.80 (s, 2H) thiazole-5-carboxylic acid 4.27 (s, 2H) 4.44 (s, 1H) 7.14 (s, 1H) 12.15 (s, 1H) 409 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 582 for Example 256 methyl-1H-pyrrol-2- C₂₀H₂₅Cl₂N₅O₇S₂ yl)carbonyl]amino}-3- NMR: 1.76 (s, 2H) 2.19 (s, 3H) methoxypiperidin-1-yl)-4-({[2- 3.06 (s, 3H) 3.38 (s, 5H) 3.44 (t, (methylsulfonyl)ethyl]amino} 3H) 3.57 (s, 1H) 3.68-3.81 (m, carbonyl)-1,3-thiazole-5- 2H) 4.26 (s, 2H) 7.16 (d, 1H) carboxylic acid 9.45-9.56 (m, 1H) 12.15 (s, 1H) 410 2-((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-{[(1,3- oxazol-2- ylmethyl)amino]carbonyl}-1,3- thiazole-5-carboxylic acid

MS (ES) MH⁺: 557 for C₂₁H₂₂Cl₂N₆O₆S; NMR: 1.76 (s, 2H) 2.19 (s, 3H) 3.38 (s, 3H) 3.45 (s, 1H) 3.57 (s, 1H) 4.26 (d, 2H) 4.65 (s, 2H) 7.11-7.24 (m, 2H) 8.09 (s, 1H) 9.98 (s, 1H) 12.16 (s, 1H) 15.92 (s, 1H) Example 239 411 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 522 for Example 240 methyl-1H-pyrrol-2- C₁₉H₂₂Cl₂FN₅O₅S; yl)carbonyl]amino}-3- NMR: 1.76 (s, 2H) 2.19 (s, 3H) methoxypiperidin-1-yl)-4-{[(2- 3.38 (s, 4H) 3.45 (s, 1H) 3.58 (s, fluoroethyl)amino]carbonyl}-1,3- 2H) 3.68 (s, 1H) 4.14 (s, 1H) thiazole-5-carboxylic acid 4.27 (s, 2H) 4.47-4.54 (m, 1H) 4.67 (t, 1H) 7.26 (d, J = 8.29 Hz, 1H) 9.55 (s, 1H) 12.29 (s, 1H) 16.19 (s, 1H) 412 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) MH⁺: 548 for Example 241 methyl-1H-pyrrol-2- C₂₁H₂₇Cl₂N₅O₆S; yl)carbonyl]amino}-3- NMR: 1.11 (d, 6H) 1.77 (s, 2H) methoxypiperidin-1-yl)-4-{[(2- 2.18 (s, 3H) 3.23 (s, 3H) 3.38 (s, hydroxy-2- 3H) 3.57 (s, 1H) 4.29 (s, 1H) methylpropyl)amino]carbonyl}- 4.76 (s, 1H) 7.18 (s, 1H) 8.94 (s, 1,3-thiazole-5-carboxylic acid 1H) 12.16 (s, 1H)

Example 413 4-{[(1-cyanocyclopropyl)amino]carbonyl}-2-((3S,4R) -4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid

To a solution of ethyl 4-{[(1-cyanocyclopropyl)amino]carbonyl}-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate (0.09 g, 0.16 mmol, Example 230) in methanol (2 mL) was added potassium carbonate (0.022 g, 0.16 mmol) and water (0.5 mL). After heating in the microwave for 30 min at 80°, reaction was complete by LCMS analysis. The reaction mixture was diluted with water and acidified with 1N HCl. After concentrating to remove methanol, the resulting white precipitate was filtered, washed with water and dried (0.071 g). MS (ES) M+H⁺: 541 for C₂₁H₂₂Cl₂N₆O₅S; NMR: 1.33-1.41 (m, 2 H) 1.64 (s, 2 H) 1.75 (s, 2 H) 2.19 (s, 3 H) 3.37 (s, 3H) 3.43 (s, 1 H) 3.57 (s, 1 H) 4.08 (s, 1 H) 4.27 (d, 2 H) 4.40 (s, 1 H) 7.16 (d, 1 H) 9.87 (s, 1 H) 12.17 (s, 1 H).

Example 414

The following Example was prepared by the procedure described in Example 413 from the starting materials (SM) indicated.

Ex Compound Data SM 414 4-{[(1-cyano-1- MS (ES) MH⁺: 543 for Example 232 methylethyl)amino]carbonyl}- C₂₁H₂₄Cl₂N₆O₅S; 2-((3S,4R)-4-{[(3,4-dichloro-5- NMR: 1.68 (s, 6 H) 1.76 (s, 2 H) methyl-1H-pyrrol-2- 2.19 (s, 3 H) 3.38 (s, 4 H) yl)carbonyl]amino}-3- 3.44 (s, 1 H) 3.56 (s, 1 H) 4.11 (s, 1 methoxypiperidin-1-yl)-1,3- H) 4.25 (s, 2 H) 7.14 (s, 1 H) thiazole-5-carboxylic acid 9.10 (s, 1 H) 12.17 (s, 1 H)

Example 415 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-N-methoxy-N-methyl-1,3-thiazole-5-carboxamide

2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (10 mg, 0.024 mmol) was dissolved in dry DMF (10 ml), HATU (9.1 mg, 0.024 mmol), triethylamine (7.27 mg, 0.072 mmol) and N,O-dimethylhydroxyamine (4.65 mg, 0.048 mmol) were added. The mixture was stirred at room temperature for 30 minutes, then was poured into cold water (30 ml), the precipitate was filtered, washed with water and collected as the desired product (off white solid, 10 mg).

MS (ESP): 465 (MH⁺) for C₁₇H₂₀Cl₂FN₅O₃S.

NMR (CDCl₃) δ: 1.87 (m, 2H); 2.19 (s, 3H); 3.07 (m, 2H); 3.21 (s, 3H); 3.72 (s, 3H); 4.01 (m, 1H); 4.30 (m, 2H); 4.96 (d, br, 1H); 7.28 (d, 1H); 7.85 (s, 1H); 12.09 (s, 1H).

The following compound was produced following the procedure described for Example 415 from Example 334 and N-methoxy amine hydrochloride.

Example 416 2-((3S,4R)-4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-N-methoxy-4-methyl-1,3-thiazole-5-carboxamide

MS (ES) MH⁺: 476 for C₁₈H₂₃Cl₂N₅O₄S; NMR: 1.66-1.79 (m, 1H), 2.17(s, 3H), 2.37 (s, 3H), 3.20-3.35 (m, buried under water peak), 3.35 (s, 3H), 33.50-3.55 (m, 1H), 3.61 (s, 3H), 3.82-3.91 (m, 1H), 4.15-4.31 (m, 2H), 7.14 (d, 1H), 10.79 (s, 1H), 12.14 (s, 1H).

Example 417 sodium 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylate

Sodium hydroxide (0.056 mL, 0.056 mmol, Acros 1N) was added to a suspension of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid (0.03 g, 0.056 mmol, Example 387) in methanol (5 mL). After stirring five minutes the reaction was homogeneous. The reaction mixture was concentrated and the resulting white solid was dried overnight (0.030 g). MS (ES) MH⁺: 534 for C₂₀H₂₄C₂N₅O₆SNa; NMR: 1.73 (s, 2 H) 2.19 (s, 3 H) 3.24 (s, 3 H) 3.32 (s, 2 H) 3.36 (s, 3 H) 3.51 (s, 1 H) 3.84 (s, 1 H) 4.22 (d, 2 H) 7.17 (d, 1 H) 12.17 (s, 1 H) 13.26 (s, 1 H).

Examples 419-423

The following Examples were prepared by the procedure described in Example 417 from the starting materials (SM) indicated.

Ex Compound Data SM 419 sodium 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 548 for Example 395 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₆Cl₂N₅O₆SNa yl)carbonyl]amino}-3- NMR: 1.04-1.15 (m, 3H) 1.71 methoxypiperidin-1-yl)-4- (s, 2H) 2.18 (s, 3H) 3.08-3.21 ({[(1S)-2-methoxy-1- (m, 3H) 3.25 (s, 3H) 3.36 (s, 4 methylethyl]amino}carbonyl)- H) 3.50 (s, 1H) 3.87 (d, 1H) 3.99 1,3-thiazole-5-carboxylate (dt, 1H) 4.11 (s, 1H) 4.22 (s, 1 H) 7.21 (d, 1H) 13.17 (d, 1H) 420 sodium 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1S)-2-methoxy-1- methylethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 582 for C₂₀H₂₄Cl₂N₅O₇S₂Na NMR: 1.67-1.78 (m, 2H) 2.18 (s, 3H) 3.00 (s, 3H) 3.10-3.21 (m, 2H) 3.24-3.31 (m, 3H) 3.36 (s, 3H) 3.47-3.60 (m, 3H) 3.85 (s, 1H) 4.10 (s, 1H) 4.17 (s, 2H) 7.17 (d, 1H) 12.16 (s, 1H) 13.71 (s, 1H) Example 409 421 sodium 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 556 for Example 410 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₁Cl₂N₆O₆SNa yl)carbonyl]amino}-3- NMR: 1.71 (d, 2H) 2.15 (s, 3H) methoxypiperidin-1-yl)-4-{[(1,3- 3.09-3.24 (m, 2H) 3.35 (s, 3H) oxazol-2- 3.49 (s, 1H) 3.84 (s, 1H) 4.16 (s, ylmethyl)amino]carbonyl}-1,3- 2H) 4.48 (d, 2H) 7.12 (s, 12H) thiazole-5-carboxylate 7.18 (d, 1H) 8.01 (s, 1H) 12.17 (s, 1H) 13.95-14.07 (m, 1H) 422 sodium 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 534 for Example 399 dichloro-5-methyl-1H-pyrrol-2- C₂₀H₂₁Cl₂FN₅O₅SNa yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1R,2S)-2- fluorocyclopropyl]amino}carbon- yl)-1,3-thiazole-5-carboxylate 423 Sodium-2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 435,437 for Example 42 dichloro-5-methyl-1H-pyrrol-2- C₁₆H₁₇Cl₂FN₄O₃S; NMR: 1.77- yl)carbonyl]amino}-3- 1.79 (m, 1H), 1.99 (m, 1H), 2.24 fluoropiperidin-1-yl)-1,3- (s, 3H), 3.25-3.27 (m, 1H), 3.74 thiazole-5-carboxylate (d, 1H), 4.16 (m, 1H), 4.22 (m, 1H), 4.38 (t, 1H), 4.83 (d, 1H), 7.19 (s, 1H), 8.13 (br d, 1H)

Example 424 N-ethylethanaminium 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylate

Diethylamine (0.0058 mL, 0.056 mmol, Aldrich) was added to a suspension of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid (0.03 g, 0.056 mmol, Example 387) in methanol (5 mL). After stirring five minutes, methylene chloride was added until solution was homogeneous. The reaction was concentrated and the resulting solid was dried overnight (0.024 g). MS (ES) MH⁺: 534 for C₂₄H₃₇Cl₂N₆O₆S; NMR: 1.16 (t, 3 H) 1.74 (s, 2 H) 2.19 (s, 3 H) 2.91 (q, 3 H) 3.25 (s, 3 H) 3.32 (s, 4 H) 3.37 (s, 3 H) 3.42 (d, 2 H) 3.53 (s, 1 H) 3.94 (s, 1 H) 4.22 (s, 2 H) 7.17 (d, 1 H).

Example 425

The following compound was synthesized according to the procedure described for Example 424.

Ex Compound Data SM 425 N-ethylethanaminium-2- ((3S,4R)-4-{[(3,4-dichloro-5- methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidin-1-yl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 435,437 for C₁₆H₁₇Cl₂FN₄O₃S; NMR: 1.14 (t, 3H), 1.81 (m, 2H), 2.21 (s, 3H), 2.84 (q, 2H), 3.34 (m, 2H), 3.86 (m, 1H), 4.30 (m, 1H), 4.89 (d, 1H), 7.32 (s, 1H), 7.61 (d, 1H) Example 42

Example 426 Potassium 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylate

An aqueous solution of potassium hydroxide (0.1 M, 4.75 ml, 0.475 mmol) was added to a solution of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 42, 200 mg, 0.475 mmol) in methanol (35 ml). The mixture was stirred for 1 h and then concentrated under reduced pressure to provide the crude salt (230 mg). The salt was dissolved in acetone/water (50 ml; 48:2) and acetone was added slowly to the stirred mixture until it became cloudy. Stirring was continued and more acetone was added very slowly over 20 min. The mixture was stored at 4° C. overnight. The solid was collected by filtration and air dried for 24 h to provide the salt (160 mg).

MS (ESP): 421 (M+H) for C₁₅H₁₅Cl₂FN₄O₃S.

¹H NMR (300 MHz, DMSO-d₆) δ: 1.75 (d, 1H); 2.04 (m, 1H); 2.24 (s, 3H); 3.34 (m, 2H); 3.75 (d, 1H); 4.20 (m, 1H); 4.39 (t, 1H); 4.83 (d, 1H); 7.17 (s, 1H); 8.18 (s, 1H); 14.12 (s, 1H).

Example 427 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylate

Tromethamine (43 mg, 0.36 mmol), 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 42, 150 mg, 0.36 mmol), methanol (50 ml) and water (5 ml) were combined and stirred at 60° C. until the mixture was a homogeneous solution (30 min). The mixture was cooled to room temperature and concentrated under reduced pressure. The crude salt (80 mg) was dissolved in ethyl acetate/methanol (8 ml; 50:50) and ethyl acetate was added slowly to the stirred solution until it became cloudy. Stirring was continued and additional ethyl acetate (˜15 ml) was added slowly to the mixture. The mixture was stored at 4° C. overnight. The solid was collected by filtration and air dried for 24 h to provide the salt (64 mg).

MS (ESP): 421 (M+H) for C₁₅H₁₅Cl₂FN₄O₃S.

¹H NMR (300 MHz, Methanol-d₄) δ: 2.00 (m, 2H); 2.25 (s, 3H); 3.33 (m, 2H); 3.30-3.55 (m, 2H); 3.67 (s, 6H); 4.10 (d, 1H); 4.35 (m, 2H); 4.90 (d, 1H); 7.57 (s, 1H).

Example 428

The following Example was prepared by the procedure described in Example 1 from the starting materials (SM) indicated in the table below.

Ex Compound Data SM 428 methyl 2-((3S,4R)-4-{[(4-chloro- MS (ESP): 419 (MH⁺) for Intermediate 261 3-fluoro-5-methyl-1H-pyrrol-2- C₁₆H₁₇ClF₂N₄O₃S yl)carbonyl]amino}-3- ¹H-NMR (CDCl₃) δ: fluoropiperidin-1-yl)-1,3- 1.96 (m, 2H); 2.25 (s, 3H); thiazole-5-carboxylate 3.37 (m 2H); 3.84 (s, 3H); 4.17 (m, 1H); 4.38 (m, 1H); 4.56 (m, 1H); 4.87 (d, br, 1H); 6.21 (m, 1H); 7.87 (s, 1H); 9.35 (s, br, 1H); ¹⁹F-NMR (CDCl₃) δ: −158(s)

Example 429

The following Example was synthesized by an analogous method to Example 35 from the starting materials (SM) given in the table below.

Ex Compound NMR m/z SM 429 2-((3S,4R)-4-{[(4-chloro-3- 1.85 (m, 2H); 2.15 (s, 3H); 405 Example fluoro-5-methyl-1H-pyrrol-2- 3.31 (m 2H); 4.0 (m, 1H); 4.31 (m, 428 yl)carbonyl]amino}-3- 2H); 4.90 (d, br, 1H); 7.43 (d, 1H); fluoropiperidin-1-yl)-1,3- 7.75 (s, 1H); 11.95 (s, br, 1H); thiazole-5-carboxylic acid ¹⁹F-NMR (CDCl₃) δ: −158(s)ppm

Examples 430-433

The following Examples were prepared by the procedure described in Example 1 from the starting materials (SM) indicated in the table below.

Ex Compound Data SM 430 Ethyl 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol- 2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(2R)-2- methoxypropyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate

MS (ES) MH: 575 for C₂₃H₃₁Cl₂N₅O₆S; NMR: 1.08 (d, 3H), 1.20 (t, 3H), 1.68-1.76 (m, 2H), 2.17 (s, 3H), 3.14-3.19 (m, 1H), 3.25 (s, 3H), 3.35 (s, 3H), 3.54 (brs, 1H), 3.90-4.05 (m, 2H), 4.15 (q, 2H), 4.20-4.30 (m, 2H), 7.15 (d, 1H), 8.32 (d, 1H), 12.16 (s, 1H) Example 191 and Intermediate 1725-162 431 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH: 575 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₃H₃₁Cl₂N₅O₆S; (2S)-2- 2-yl)carbonyl]amino}-3- NMR: 1.09 (d, 3H), 1.21 (t, methoxypropan-1- methoxypiperidin-1-yl)-4- 3H), 1.68-1.76 (m, 2H), 2.18 amine hydrochloride ({[(2S)-2- (s, 3H), 3.15-3.21 (m, 1H), (1725-163) methoxypropyl]amino}carbonyl)- 3.26 (s, 3H), 3.36 (s, 3H), 1,3-thiazole-5-carboxylate 3.54 (brs, 1H), 3.95-4.05 (m, 2H), 4.16 (q, 2H), 4.20-4.30 (m, 2H), 7.15 (d, 1H), 8.32 (d, 1H), 12.16 (s, 1H) 432 Ethyl 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 576 for Example 191 and dichloro-5-methyl-1H-pyrrol- C₂₃H₃₁Cl₂N₅O₆S; (2R)-1- 2-yl)carbonyl]amino}-3- NMR: 1.08 (d, 3H), 1.21 (t, methoxypropan-2- methoxypiperidin-1-yl)-4- 3H), 1.68-1.76 (m, 2H), 2.17 amine hydrochloride ({[(1R)-2-methoxy-1- (s, 3H), 3.14-3.20 (m, 1H), (1725-177) methylethyl]amino}carbonyl)- 3.25 (s, 3H), 3.35 (s, 3H), 1,3-thiazole-5-carboxylate 3.54 (brs, 1H), 3.95-4.05 (m, 2H), 4.16 (q, 2H), 4.20-4.30 (m, 2H), 7.14 (d, 1H), 8.30 (d, 1H), 12.15 (s, 1H) 433 Cis(±)-methyl 2-(3-azido-4- 1.8 (m, 2H), 2.19 (s, 3H), Intermediate 272 and {[(3,4-dichloro-5-methyl-1H- 3.35 (m, 1H), 3.6 (d, 1H), methyl 2-bromo-1,3- pyrrol-2- 3.75 (s, 3H), 3.95 (d, 1H), thiazole-5- yl)carbonyl]amino}piperidin- 4.24 (m, 3H), 7.23 (d, 1H), carboxylate 1-yl)-1,3-thiazole-5- 7.86 (s, 1H), 12.1 (s, 1H). carboxylate

Examples 434-437

The following Examples were synthesized by an analogous method to Example 35 from the starting materials (SM) given in the table below.

Ex Compound NMR m/z SM 434 2-((3S,4R)-4-{[(3,4-Dichloro- 1.07 (d, 3H), 1.70-1.76 (m, 2H), 546 Example 5-methyl-1H-pyrrol-2- 2.17 (s, 3H), 3.25 (s, 3H), 3.36 (s, 430 yl)carbonyl]amino}-3- 3H), 3.37-3.50 (m, 2H), 3.55 (brs, methoxypiperidin-1-yl)-4- 1H), 4.20-4.30 (m, 2H), 4.45 (brs, ({[(2R)-2- 1H), 7.16 (d, 1H), 8.98 (d, 1H), methoxypropyl]amino}carbonyl)- 12.13 (s, 1H), 16.30 (s, 1H) 1,3-thiazole-5-carboxylic acid 435 2-((3S,4R)-4-{[(3,4-Dichloro- 5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(2S)-2- methoxypropyl]amino}carbonyl)- 1,3-thiazole-5-carboxylic acid

1.16 (d, 3H), 1.70-1.76 (m, 2H), 2.18 (s, 3H), 3.23 (s, 3H), 3.37 (s, 3H), 3.44-3.50 (m, 2H), 3.55 (brs, 1H), 4.20-4.30 (m, 2H), 4.45 (brs, 1H), 7.16 (d, 1H), 8.98 (d, 1H), 12.14 (s, 1H), 16.31 (s, 1H) 546 Example 431 436 2-((3S,4R)-4-{[(3,4-Dichloro- 1.16 (d, 3H), 1.70-1.76 (m, 2H), 547 Example 5-methyl-1H-pyrrol-2- 2.17 (s, 3H), 3.26 (s, 3H), 3.38 (s, 432 yl)carbonyl]amino}-3- 3H), 3.46-3.52 (m, 2H), 3.55 (brs, methoxypiperidin-1-yl)-4- 1H), 4.20-4.30 (m, 2H), 4.45 (brs, ({[(1R)-2-methoxy-1- 1H), 7.16 (d, 1H), 8.96 (d, 1H), methylethyl]amino}carbonyl)- 12.14 (s, 1H), 16.31 (s, 1H) 1,3-thiazole-5-carboxylic acid 437 Cis(±)-2-(3-azido-4-{[(3,4- .8 (m, 2H), 2.2 (s, 3H), 3.3 (m, 444 Example dichloro-5-methyl-1H-pyrrol-2- 1H), 3.6 (d, 1H), 3.9 (d, 1H), 4.24 433 yl)carbonyl]amino}piperidin-1- (m, 3H), 7.23 (d, 1H), 7.7 (s, 1H), yl)-1,3-thiazole-5-carboxylic 12.1 (s, 1H), 12.7 (S, 1H) acid

Examples 438-440

The following Examples were prepared by the procedure described in Example 417 from the starting materials (SM) indicated

Ex Compound Data SM 438 sodium 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 547 for Example 434 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₆Cl₂N₅O₆S; NMR: 1.07 (d, yl)carbonyl]amino}-3- 3H), 1.60-1.75 (m, 2H), 2.14 (s, methoxypiperidin-1-yl)-4- 3H), 3.10-3.19 (m, 3H), 3.24 (s, ({[(2R)-2- 3H), 3.34 (s, 3H), 3.47 (brs, 1H), methoxypropyl]amino}carbonyl)- 3.81-3.85 (m, 1H), 3.90-4.00 (m, 1,3-thiazole-5-carboxylate 1H), 4.05-4.20 (m, 2H), 7.17 (d, 1H), 12.16 (brs, 1H), 13.22 (d, 1H) 439 Sodium 2-((3S,4R)-4-{[(3,4- MS (ES) MH⁺: 547 for Example 435 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₂₆Cl₂N₅O₆S; NMR: 1.07 (d, yl)carbonyl]amino}-3- 3H), 1.60-1.75 (m, 2H), 2.17 (s, methoxypiperidin-1-yl)-4- 3H), 3.10-3.22(m, 3H), 3.24 (s, ({[(2S)-2- 3H), 3.35 (s, 3H), 3.49 (brs, 1H), methoxypropyl]amino}carbonyl)- 3.81-3.85 (m, 1H), 3.90-4.00 (m, 1,3-thiazole-5-carboxylate 1H), 4.05-4.20 (m, 2H), 7.15 (d, 1H), 12.15 (brs, 1H), 13.22 (d, 1H) 440 Sodium 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4- ({[(1R)-2-methoxy-1- methylethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 547 for C₂₁H₂₆Cl₂N₅O₆S; NMR: 1.07 (d, 3H), 1.65-1.73 (m, 2H), 2.17 (s, 3H), 3.10-3.22 (m, 3H), 3.24 (s, 3H), 3.35 (s, 3H), 3.49 (brs, 1H), 3.81-3.85 (m, 1H), 3.90-4.00 (m, 1H), 4.05-4.20 (m, 2H), 7.17 (d, 1H), 12.18 (brs, 1H), 13.19 (d, 1H) Example 436

Preparation of Starting Materials Intermediate 83-278 Intermediate 83 Cis(±)-ethyl (4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate

A solution of 167 mg (0.9 mmol) of Cis(±)-ethyl (4-amino-3-methylpiperidine-1-carboxylate (Intermediate 152), 235 μl (1.25 mmol) diisopropylethylamine and 280 mg (1.35) of 3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl chloride (Intermediate 202) was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and washed with aqueous Na₂CO₃ and brine. Drying MgSO4 and removal of solvent gave an oil that was purified by chromatography (100% CH₂Cl₂ followed by gradient elution to 100% EtOAc) to afford 145 mg of product. MS (ES)(MH⁺): 362 for C₁₅H₂₁Cl₂N₃O₃; NMR (d₆-DMSO): 0.8 (d, 3H), 1.2 (t, 3H), 1.65 (m, 2H), 1.9 (m, 1H), 2.2 (s, 3H), 3.5 (m, 1H), 4.0 (m, 2H), 4.1 (m, 1H), 7.1 (d, 1H), 12.0 (s, 1H).

Intermediates 84-114

The following Intermediates were synthesized by an analogous method to Intermediate 37 or Intermediate 83 from the starting materials (SW) given in the table below.

Int Compound Data SM 84 Cis(±)-tert-butyl 4-{[(3,4- N/A Intermediate 72 dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- [(methylthio)methyl]piperidine- 1-carboxylate 85 Cis(±)-tert-butyl-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- (methylthio)piperidine-1- carboxylate

MS (ESP): 420.1 (M −+0H) for C₁₇H₂₅Cl₂N₃O₃S; NMR: 1.40 (s, 9H); 1.45-1.70 (m, 2H); 2.10 (s, 3H); 2.18 (s, 3H); 2.80-3.20 (m, 2H); 3.31 (m, 1H); 3.90 (m, 2H); 4.30 (m, 1H); 7.15 (d, 1H); 12.13 (s, 1H) Intermediate 184 and Intermediate 1 86 Cis(±)-ethyl 3-(benzyloxy)-4- MS (ESP): 454 (M ++0H) for Intermediate 158 {[(3,4-dichloro-5-methyl-1H- C₂₁H₂₅Cl₂N₃O₄; NMR: 1.20 and Intermediate 1 pyrrol-2- (q, 3H); 1.70 (m, 2H); 2.15 (s, yl)carbonyl]amino}piperidine-1- 3H); 3.05 (m, 2H); 3.68 (s, carboxylate 1H); 4.00 (m, 3H); 4.15 (m, 1H); 4.40 (m, 2H); 4.70 (d, 1H); 7.08 (d, 1H); 7.30 (m, 5H); 12.06 (s, 1H). 87 Cis(±)-ethyl 4-{[(3,4-dichloro-5- MS (ESP): 424 (M + Na) for Intermediate 256 methyl-1H-pyrrol-2- C₁₇H₂₁Cl₂N₃O₄; ¹H NMR and Intermediate 1 yl)carbonyl]amino}-3-(prop-2- (300 MHz, CDCl₃) δ: 1.27 (t, yn-1-yloxy)piperidine-1- 3H); 1.79 (m, 2H); 2.27 (s, carboxylate 3H); 2.40 (t, 1H); 2.90 (m, 2H); 3.85 (m, 1H); 4.10-4.55 (m, 7H); 7.25 (m, 1H); 9.53 (s, 1H). 88 Trans-(±)tert-butyl 4-{[(3,4- MS (ES) MH⁺: 392 for Intermediate 185 dichloro-5-methyl-1H-pyrrol- C₁₆H₂₃Cl₂N₃O₄; NMR: 1.45 and Intermediate 1 2yl)carbonyl]amino}3- (s, 9H), 1.54 (m, 1H), 2.02 hydroxypiperidine-1- (m, 1H), 2.27 (s, 3H), 2.67 carboxylate (dd, 1H), 2.84 (brt, 1H), 3.34 (m, 1H), 3.50 (m, 1H), 3.90 (m, 1H), 4.11 (m, 1H), 4.27 (m, 1H), 6.75 (brd, 1H), 10.06 (br s, 1H) 89 tert-butyl (3S,4R)-4-{[(3-chloro- MS (ES) MH⁺: 360 for Intermediate 196 5-methyl-1H-pyrrol-2- C₁₆H₂₃ClFN₃O₃ and Intermediate 64 yl)carbonyl]amino}- 3-fluoropiperidine-1-carboxylate 90 tert-butyl (3S,4R)-4-{[(4-bromo- 5-methyl-1H-pyrrol-2-yl) carbonyl]amino}-3- fluoropiperidine-1-carboxylate

MS (ESN): 404 (M − 1) for C₁₆H₂₃BrN₃O₃ NMR (CDCl₃) δ: 1.47 (t, 9H); 1.80 (m, 2H); 2.26 (s, 3H); 2.81 (s, 3H); 2.96 (m, 1H); 4.27 (m, 1H); 4.65 (d, br, 1H); 6.11 (d, 1H); 6.59 (s, 1H); 9.97 (s, br, 1H) Intermediate 197 and Intermediate 64 91 tert-butyl (3S,4R)-4-{[(4-bromo- MS (ES) MH⁺: 440 for Intermediate 198 3-chloro-5-methyl-1H-pyrrol-2- C₁₆H₂₂BrClFN₃O₃ and Intermediate 64 yl)carbonyl]amino}-3- NMR (CDCl₃) δ: 1.47 (s, fluoropiperidine-1-carboxylate 9H); 1.85 (m, 2H); 2.29 (s, 3H); 2.85 (m, 2H); 4.24 (m, 2H); 4.50 (m, 1H); 4.72 (d, br, 1H); 6.96 (d, 1H); 9.30 (s, br, 1H) 92 Cis(±)-Ethyl (4-{[(3,4-dichloro- MS (ES) MH⁻: 420 for Intermediate 159 5-methyl-1H-pyrrol-2- C₁₇H₂₅Cl₂N₄O₅ and Intermediate 1 yl)carbonyl]amino}-3-(2- methoxyethoxy)piperidine-1- carboxylate 93 Cis(±)-Ethyl 4-{[(3,4-dichloro- MS (ES) MH⁺: 436 for Intermediate 160 5-methyl-1H-pyrrol-2- C₁₈H₂₇Cl₂N₃O₅ and Intermediate 1 yl)carbonyl]amino}-3-(2- methoxypropoxy)piperidine-1- carboxylate 94 Cis(±)-Ethyl 4-{[(3,4-dichloro- MS (ES) MH⁺: 422 for Intermediate 161 5-methyl-1H-pyrrol-2- C₁₇H₂₅Cl₂N₃O₅ and Intermediate 1 yl)carbonyl]amino}-3-(2- hydroxypropoxy)piperidine-1- carboxylate 95 tert-Butyl (3S,4R)-4-{[(4- chloro-1H-pyrrol-2- yl)carbonyl]amino}-3- fluoropiperidine-1-carboxylate

C₁₅H₂₁ClFN₃O₃ NMR: 1.39 (s, 9H), 1.50-1.60 (m, 1H), 1.69-1.80 (m, 1H), 2.73-3.11 (m, 2H), 3.95-4.23 (m, 3H), 4.71 (d, 1H), 6.94- 6.96 (m, 2H), 8.03 (d, 1H), 11.78 (s, 1H) 2,2,2-trichloro-1- (4-chloro-1H- pyrrol-2- yl)ethanone (Tett lett. 27, 2505-2508, 1979) and Intermediate 64 96 tert-Butyl (3S, 4R)-4- {[(4,5- C₁₅H₂₁ClFN₃O₃ Intermediate 203 dichloro-1H-pyrrol-2- NMR: 1.39 (s, 9H), 1.50-1.60 and Intermediate 64 yl)carbonyl]amino}-3- (m, 1H), 1.69-1.80 (m, 1H), fluoropiperidine-1-carboxylate 2.73-3.11 (m, 2H), 3.95-4.23 (m, 3H), 4.71 (d, 1H), 6.94- 6.96 (m, 2H), 8.03 (d, 1H), 11.78 (s, 1H) 97 Ethyl (3S,4R)-4-{[(4-chloro-5- MS (ES) MH⁺: for Intermediate 6 methyl-1H-pyrrol-2- C₁₅H₂₂ClN₃O₄; NMR: 1.18 (t, and Intermediate 25 yl)carbonyl]amino}-3- J = 7.06 Hz, 3H), 1.48 (d, methoxypiperidine-1- J = 3.58 Hz, 1H), 1.75 (td, carboxylate J = 12.29, 7.82 Hz, 1H), 2.10- 2.18 (m, 3H), 2.95 (d, J = 13.38 Hz, 2H), 3.20-3.27 (m, 3H), 3.27-3.35 (m, 2H), 3.38 (s, 1H), 3.97-4.09 (m, J = 10.53, 7.08, 7.08, 3.39 Hz, 2H), 4.19 (s, 1H), 6.88 (d, J = 2.64 Hz, 1H), 7.62 (d, J = 7.91 Hz, 1H), 11.60 (s, 1H) 98 Cis(±)-ethyl-4-{[(4-chloro-3,5- MS (ES) MH⁺: 358 for Intermediate 195 dimethyl-1H-pyrrol-2- C₁₆H₂₄ClN₃O₄. and Intermediate 26 yl)carbonyl]amino}-3- methoxypiperidine-1- carboxylate 99 tert-butyl (Cis(±)-3-chloro-4- 1.40 (s, 9H), 1.67 (m, 2H), Intermediate 1 and {[(3,4-dichloro-5-methyl-1H- 2.19 (s, 3H), 2.68 (m, 1H), Intermediate 162 pyrrol-2- 3.43 (m, 1H), 4.02 (m, 1H), yl)carbonyl]amino}piperidine-1- 4.17 (m, 1H), 4.36 (m, 1H), carboxylate 4.58 (s, 1H), 7.05 (d, 1H), 12.12 (s, 1H) 100 tert-butyl (3S,4R)-4-[({4-chloro- 3-[(E)-(methoxyimino)methyl]- 5-methyl-1H-pyrrol-2- yl}carbonyl)amino]-3- fluoropiperidine-1-carboxylate

MS (ES) MH⁺: 415 for C₁₈H₂₆ClFN₄O₄; NMR: 1.40 (s, 9H), 1.70 (m, 2H), 2.34 (s, 3H), 3.29 (m, 1H), 3.31 (s, 3H), 3.35 (m, 1H), 3.99 (m, 1H), 4.24 (m, 2H), 4.78 (d, 1H), 7.19 (d, 1H), 8.02 (s, 1H), 12.11 (s, 1H) Intermediate 199 and Intermediate 64 101 tert-butyl Cis(±)-3-chloro-4- 1.40 (s, 9H), 1.54 (m, 1H), 162 and {[(4-chloro-5-methyl-1H-pyrrol- 1.83 (m, 1H), 2.14 (s, 3H), Intermediate 6 2-yl)carbonyl]amino}piperidine- 3.28 (m, 1H), 3.41 (m, 1H), 1-carboxylate 4.02-4.22 (m, 3H), 4.56 (s, 1H), 6.89 (s, 1H), 7.80 (d, 1H), 11.63 (s, 1H) 102a Cis(±)-ethyl (4-{[(3,4-dichloro- MS (ES) (MH⁺): 362 for Intermediate 202 5-methyl-1H-pyrrol-2- C₁₅H₂₁Cl₂N₃O₃; NMR (d₆- and Intermediate 164 yl)carbonyl]amino}-2- DMSO): 0.8 (d, 3H), 1.2 (t, methylpiperidine-1-carboxylate 3H), 1.65 (m, 2H), 1.9 (m, 1H), 2.2 (s, 3H), 3.5 (m, 1H), 4.0 (m, 2H), 4.1 (m, 1H), 7.1 (d, 1H), 12.0 (s, 1H) 102b Cis(±)-ethyl (4-{[(4-chloro-3- MS (ES) (MH⁺): 369 for Intermediate 200 cyano-5-methyl-1H-pyrrol-2- C₁₆H₂₁ClN₄O₄; NMR (d₆- and Intermediate 21 yl)carbonyl]amino}-3- DMSO): 1.2 (t, 3H), 2.2 (s, methoxypiperidine-1- 3H), 2.8-3.1 (m, 2H), 3.3 (s, carboxylate 3H), 3.4 (m, 1H), 3.8-4.3 (m 5H), 7.7 (d, 1H), 12.7 (s, 1H) 103 tert-butyl (3S,4R)-4-{[(4-chloro- MS (ES) (MH⁺): 383 for Intermediate 200 3-cyano-5-methyl-1H-pyrrol-2- C₁₇H₂₂ClFN₄O₃; NMR (d₆- and Intermediate 59 yl)carbonyl]amino}-3- DMSO): 1.4 (s, 9H), 1.7 (m, fluoropiperidine-1-carboxylate 2H), 2.2 (s, 3H), 3.8-4.2 (m, 4H), 4.8 (d, 1H), 8.0 (d, 1H), 12.5 (s, 1H) 104 tert-butyl (3S,4R)-4-{[(3,5- MS (ES) (MH⁺): 394 for Intermediate 201 dichloro-4-methyl-1H-pyrrol-2- C₁₆H₂₂Cl₂FN₃O₃; NMR (d₆- and Intermediate 59 yl)carbonyl]amino}-3- DMSO): 1.4 (s, 9H), 1.6-1.8 fluoropiperidine-1-carboxylate (m, 2H), 1.9 (s, 3H), 2.9 (m, 2H), 4.0-4.3 (m, 3H), 4.8 (d, 1H), 7.3 (d, 1H), 12.5 (s, 1H) 105 Cis(±)-Ethyl3- (cyclopropylmethoxy)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}piperidine-1- carboxylate

MS (ESI) M: 418 for C₁₈H₂₅Cl₂N₃O₄; NMR: 0.22 (m, 2H), 0.50 (m, 2H), 1.04 (m, 1H), 1.24 (t, 3H), 1.69 (m, 2H), 2.24 (s, 3H), 2.87- 3.09 (m, 2H), 3.28 (m, 1H), 3.59 (bs, 1H), 3.92-4.36 (m, 5H), 7.20 (m, 1H), 12.21 (bs, 1H) Interemdiate 165 and Intermediate 1 106 Cis(±)-ethyl 4-{[(3,4-dichloro-5- MS (ESI) M: 461 for Intermediate 166 methyl-1H-pyrrol-2- C₁₈H₂₂Cl₂N₄O₄S; NMR and Intermediate 1 yl)carbonyl]amino}-3-(1,3- (DMSO): 1.10 (m, 3H), 1.65 thiazol-2-ylmethoxy)piperidine- (m, 2H), 2.16 (s, 3H), 2.82- 1-carboxylate 3.10 (m, 2H), 3.79 (bs, 1H), 3.97 (m, 3H), 4.21 (dt, 1H), 4.35 (t, 1H), 4.78 (d, 1H), 4.95 (d, 1H), 7.10 (d, 1H), 7.72 (dd, 2H), 12.12 (bs, 1H) 107 Cis(±)-Ethyl (rel 3S,4R)-4- MS (ES) MH⁺: 392, 394 for Intermediate 257 {[(3,4-dichloro-5-methyl-1H- C₁₆H₂₃Cl₂N₃O₄; NMR: 1.04- and Intermediate 1 pyrrol-2-yl)carbonyl]amino}-3- 1.21 (m, 6H); 1.60 (m, 2H); ethoxypiperidine-1-carboxylate 2.17 (s, 3H); 2.95 (m, 2H); 3.48 (br s, 1H); 3.65 (m, 1H); 3.92 (br s, 1H); 3.98-4.05 (m, 2H); 4.09-4.25 (m, 2H); 7.09 (d, 1H) 12.14 (s, 1H) 108 1-tert-butyl 3-methyl 4-{[(3,4- MS (ES) MH⁺: 434, 436 for Intermediate 167 dichloro-5-methyl-1H-pyrrol-2- C₁₈H₂₅Cl₂N₃O₅; NMR and Intermediate 1 yl)carbonyl]amino}piperidine- (CDCl₃): 1.45 (s, 9H), 1.60 1,3-dicarboxylate (m, 1H), 2.16 (m, 1H), 2.27 (s, 3H), 2.45 (dt, 1H), 2.93 (m, 1H), 3.10 (m, 1H), 3.66 (s, 3H), 4.05 (m, 1H), 4.29 (m, 2H), 6.68 (d, 1H), 9.66 (s, 1H) 109 1-(tert-butoxycarbonyl)-4- MS (ES) MH⁺: 420, 422 for Intermediate 108 {[(3,4-dichloro-5-methyl-1H- C₁₇H₂₃Cl₂N₃O₅. and Intermediate 1 pyrrol-2- yl)carbonyl]amino}piperidine-3 - carboxylic acid 110 Cis(±)tert-butyl 4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- (morpholin-4- ylcarbonyl)piperidine-1- carboxylate

MS (ES) MH⁺: 489, 491 for C₂₁H₃₀Cl₂N₄O₅; NMR: 1.40 (s, 9H), 1.54 (m, 1H), 1.82 (m, 1H), 2.15 (s, 3H), 2.81 (broad s, 2H), 3.14 (dt, 1H), 3.24-3.40 (m, 2H [under H₂O peak]), 3.41-3.68 (m, 6H), 3.93 (m, 2H), 4.24 (m, 1H), 7.14 (d, 1H), 11.98 (s, 1H) Intermediate 109 and Intermediate 1 111 Trans(±)tert-butyl 4-{[(3,4- MS (ES) MH⁺: 489, 491 for Intermediate 109 dichloro-5-methyl-1H-pyrrol-2- C₂₁H₃₀Cl₂N₄O₅; NMR: 1.37 and Intermediate 1 yl)carbonyl]amino}-3- (s, 9H), 1.64 (m, 1H), 2.11 (morpholin-4- (m, 1H), 2.16 (s, 3H), 3.14 ylcarbonyl)piperidine-1- (m, 1H), 3.18-3.68 (m, 11H carboxylate [under H₂O peak]), 3.73 (dd, 1H), 4.37 (m, 1H), 7.24 (d, 1H), 12.08 (s, 1H) 112 Cis(±)ethyl 3-(2-tert-butoxy-2- MS (ES) MH⁺: 478, 480 for Intermediate 240 oxoethoxy)-4-{[(3,4-dichloro-5- C₂₀H₂₉Cl₂N₃O₆; NMR: 1.17 and Intermediate 1 methyl-1H-pyrrol-2- (t, 3H), 1.41 (s, 9H), 1.90 (m, yl)carbonyl]amino}piperidine-1- 1H), 2.16 (s, 3H), 2.78-3.06 carboxylate (m, 3H), 3.46 (m, 1H), 3.74 (m, 1H), 3.94 (m, 1H), 4.03 (q, 2H), 4.09 (s, 2H), 4.12 (m, 1H), 7.39 (d, 1H), 11.97 (s, 1H) 113 Trans(±)ethyl 3-(2-tert-butoxy- NMR: 1.17 (t, 3H), 1.38 (s, Intermediate 240 2-oxoethoxy)-4-{[(3,4-dichloro- 9H), 1.58 (m, 1H), 1.68 (m, and Intermediate 1 5-methyl-1H-pyrrol-2- 1H), 2.17 (s, 3H), 2.81-3.02 yl)carbonyl]amino}piperidine-1- (m, 2H), 3.66 (m, 1H), 3.86- carboxylate 4.27 (m, 7H), 7.40 (d, 1H), 12.07 (s, 1H) 114 Ethyl 3-{[tert- MS (ES)MH⁺: 478, 480 for Intermediate 112 butyl(dimethyl)silyl]oxy}-4- C₂₀H₃₃Cl₂N₃O₄Si; NMR: - and Intermediate 1 {[(3,4-dichloro-5-methyl-1H- 0.07 (s, 3H), 0.07 (s, 3H), pyrrol-2- 0.83 (s, 9H), 1.16 (t, 3H), yl)carbonyl]amino}piperidine-1- 1.56 (m, 1H), 1.72 (m, 1H), carboxylate 2.17 (s, 3H), 3.04 (m, 2H), 3.85-4.11 (m, 6H), 6.66 (m, 1H), 12.12 (s, 1H)

Intermediates 115-144

The following Intermediates were synthesized by an analogous method to Intermediate 50 or Intermediate 74 from the starting materials (SM) given in the table below.

Int Compound Data SM 115 Cis(±)-3,4-dichloro-N-[3- (hydroxymethyl)piperidin-4- yl]-5-methyl-1H-pyrrole-2- carboxamide hydrochloride

MS (ES) MH⁺: 306, 308 for C₁₂H₁₇Cl₂N₃O₂. Intermediate 71 116 Cis(±)-3,4-dichloro-5-methyl- N-{3- [(methylthio)methyl]piperidin- 4-yl}-1H-pyrrole-2- carboxamide hydrochloride MS (ES) MH⁺: 336, 338 for C₁₃H₁₉Cl₂N₃OS. Intermediate 84 117 Cis(±)-3,4-dichloro-5-methyl- MS (ESP): 463.1 (M + H) for Intermediate N-[3-(methylthio)piperidin-4- C₁₇H₂₀Cl₂N₄O₃S₂; NMR: 1.90 (m, 85 yl]-1H-pyrrole-2- 2H); 2.14 (s, 3H); 2.28 (s, 3H); 3.28- carboxamide 3.45 (m, 2H); 3.74 (s, 3H); 3.77 (m, 1H); 3.95 (m, 2H); 4.44 (m, 1H); 7.25 (d, 1H); 7.85 (s, 1H); 12.14 (s, 1H) 118 Cis(±)-N-[3- MS (ESP): 382 (M + H) for Intermediate (benzyloxy)piperidin-4-yl]- C₁₈H₂₁Cl₂N₃O₂ 86 3,4-dichloro-5-methyl-1H- pyrrole-2-carboxamide 119 Cis(±)-3,4-dichloro-5-methyl- MS (ESP): 330 (M + H) for Intermediate N-[3-(prop-2-yn-1- C₁₄H₁₇Cl₂N₃O₂ 87 yloxy)piperidin-4-yl]-1H- pyrrole-2-carboxamide 120 Trans(±)3,4-dichloro-N-[3- hydroxypiperidin-4-yl]-5- methyl-1H-pyrrole-2- carboxamide trifluoroacetate

MS (ES) MH⁺: 292 for C₁₁H₁₅Cl₂N₃O₂ Intermediate 88 121 3-chloro-N-[(3S,4R)-3- MS (ES) MH⁺: 260 for Intermediate fluoropiperidin-4-yl]-5- C₁₁H₁₅ClFN₃O; 1.91 (m, 2H); 2.17 (s, 89 methyl-1H-pyrrole-2- 3H); 3.13 (m, 1H); 3.35 (m, 2H); 3.57 carboxamide (s, 1H); 4.35 (m, 1H); 5.05 (d, br, 1H); 5.96 (s, 1H); 7.26 (d, 1H); 8.67 (br, 1H); 9.16 (br, 1H); 11.70 (s, br, 1H) 122 4-bromo-N-[(3S,4R)-3- MS (ES) MH⁺: 306 for C₁₁H₁₅BrN₃O Intermediate fluoropiperidin-4-yl]-5- 90 methyl-1H-pyrrole-2- carboxamide 123 4-bromo-3-chloro-N- MS (ES) MH⁺: 340 for C₁₁H₁₄BrN₃O Intermediate [(3S,4R)-3-fluoropiperidin-4- NMR δ: 1.91 (m, 2H); 2.20 (s, 3H); 91 yl]-5-methyl-1H-pyrrole-2- 3.13 (m, 1H); 3.35 (m, 2H); 3.62 (m, carboxamide 1H); 4.35 (m, 1H); 5.05 (d, br, 1H); 7.39 (d, 1H); 8.60 (s, br, 1H); 8.99 (s, br, 1H); 12.17 (s, br, 1H) 124 Cis(±)-3,4-dichloro-N-[(3-(2- MS (ES) MH⁺: 350 for C₁₄H₂₁Cl₂N₃O₃ Intermediate methoxyethoxy)piperidin-4- 92 yl]-5-methyl-1H-pyrrole-2- carboxamide 125 Cis(±)-3,4-Dichloro-N-[3-(2- methoxypropoxy)piperidin-4- yl]-5-methyl-1H-pyrrole-2- carboxamide

MS (ES) MH⁺: 364 for C₁₅H₂₃Cl₂N₃O₃ Intermediate 93 126 Cis(±)-3,4-Dichloro-N-3-(2- MS (ES): MH⁺: 350 for Intermediate hydroxypropoxy)piperidin-4- C₁₄H₂₁Cl₂N₃O₃; 94 yl]-5-methyl-1H-pyrrole-2- carboxamide 127 4-Chloro-N-[(3S,4R)-3- MS (ES) MH⁺: 246 for C₁₀H₁₃ClFN₃O Intermediate fluoropiperidin-4-yl]-1H- 95 pyrrole-2-carboxamide hydrochloride 128 4,5-dichloro-N-[(3S,4R)-3- MS (ES) MH⁺: 280 for Intermediate fluoropiperidin-4-yl]-1H- C₁₀H₁₂Cl₂FN₃O 96 pyrrole-2-carboxamide hydrochloride 129 4-chloro-N--[(3S,4R)-(3- 1.41 (s, 1H), 1.67 (s, 1H), 2.13 (s, 3H), Intermediate methoxypiperidin-4-yl)]1-5- 2.47 (s, 1H), 2.55 (s, 1H), 2.86 (s, 1H), 97 methyl-1H-pyrrole-2- 3.08 (d, J = 13.19 Hz, 1H), 3.25 (s, 3H), carboxamide 3.31 (s, 1H), 6.89 (d, J = 2.45 Hz, 1H), 7.52 (s, 1H), 11.59 (s, 1H) 130 Cis(±)-4-chloro-N-[(3S,4R)- 3-methoxypiperidin-4-yl]-3,5- dimethyl-1H-pyrrole-2- carboxamide

MS (ES) MH⁺: 287 for C₁₃H₂₀ClN₃O₂. Intermediate 98 131 3,4-dichloro-N-[Cis(±)-3- MS (ES) MH⁺: 310 for C₁₁H₁₄Cl₃N₃O Intermediate chloropiperidin-4-yl]-5- 99 methyl-1H-pyrrole-2- carboxamide hydrochloride 132 4-chloro-N-[(3S,4R)-3- MS (ES) MH⁺: 317 for Intermediate fluoropiperidin-4-yl]-3-[(E)- C₁₇H₁₈ClFN₄O₂ 100 (methoxyimino)methyl]-5- methyl-1H-pyrrole-2- carboxamide hydrochloride 133 Cis(±)-3-chloro-N-[3- MS (ES) MH⁺: 276 for C₁₁H₁₅Cl₂N₃O Intermediate chloropiperidin-4-yl]-5- 101 methyl-1H-pyrrole-2- carboxamide hydrochloride 134 Cis(±)-3,4-dichloro-5-methyl- MS (ES) (MH⁺): 290 for Intermediate N-[(3-methylpiperidin-4-yl]- C₁₂H₁₇Cl₂N₃O. 83 1H-pyrrole-2-carboxamide 135 Cis(±)-3,4-dichloro-5-methyl- N-[2-methylpiperidin-4-yl]- 1H-pyrrole-2-carboxamide

MS (ES) (MH⁺): 290 for C₁₂H₁₇Cl₂N₃O. NMR: 1.0 (d, 3H), 1.2-1.4 (m, 1H), 1.7-1.9 (m, 1H), 2.2 (s, 3H), 2.5-2.7 (m, 2H), 3.0 (m, 1H), 3.3 (m, 1H), 3.7- 3.8 (m, 1H), 7.1 (d, 1H) Intermediate 101 136 Cis(±)-4-chloro-3-cyano-N- MS (ES) (MH⁺): 297 for Intermediate [(3-methoxypiperidin-4-yl]-5- C₁₂H₁₇Cl₂N₃O₂. 102 methyl-1H-pyrrole-2- NMR: 1.6-1.9 (m, 2H), 2.2 (s, 3H), 2.8 carboxamide (m, 2H), 3.0 (m, 1H), 3.3 (s, 3H), 3.5 (s, 1H), 4.15 (m, 1H), 7.7 (d, 1H), 8.7 (s, broad, 1H) 137 4-chloro-3-cyano-N-[(3S,4R)- MS (ES) (MH⁺): 285 for Intermediate 3-fluoropiperidin-4-yl]-5- C₁₁H₁₄Cl₂FN₃O. 103 methyl-1H-pyrrole-2- NMR: 1.6 (m, 2H), 2.2 (s, 3H), 2.3 (m, carboxamide 1H), 2.3 (m, 1H), 2.5-3.0 (m, 2H), 3.1- 3.3 (m, 1H), 3.5 (s, 1H), 4.0-4.2 (dd, 1H), 4.7 (d, 1H), 7.9 (d, 2H) 138 (3S,4R)-4-{[(3,5-dichloro-4- MS (ES) (MH⁺): 294 for Intermediate methyl-1H-pyrrol-2- C₁₁H₁₄Cl₂FN₃O. 104 yl)carbonyl]amino}-3- NMR: 1.9 (s, 3H), 3.0-3.7 (m, 4H), 4.3 fluoropiperidinium chloride (m, 1H), 5.0 (d, 1H), 7.65 (d, 1H), 8.7 (s, broad, 1H), 9.4 (s, broad, 1H), 12.7 (s, 1H) 139 Cis(±)-3,4-dichloro-N-[3- MS (ES) MH⁺: 347 for Intermediate (cyclopropylmethoxy)piperidin- C₁₅H₂₁Cl₂N₃O₂; NMR: 0.17 (m, 2H), 105 4-yl]-5-methyl-1H-pyrrole- 0.44 (m, 2H), 1.01 (m, 1H), 1.34 (s, 2-carboxamide 1H), 1.62 (m, 2H), 2.17 (s, 3H), 2.55- 2.70 (m, 2H), 2.89 (m, 2H), 3.10-3.23 (m, 2H), 3.38-3.49 (m, 1H), 4.09 (m, 1H), 7.12 (d, 1H), 12.10 (bs, 1H). 140 Cis(±)-3,4-dichloro-5-methyl- N-[3-(1,3-thiazol-2- ylmethoxy)piperidin-4-yl]- 1H-pyrrole-2-carboxamide

MS (ESI) M: 389 for C₁₅H₁₈Cl₂N₄O₂S Intermediate 106 141 Cis(±)-3,4-Dichloro-N-[(rel MS (ES): MH⁺: 320 for Intermediate 3S,4R)-3-ethoxypiperidin-4- C₁₃H₁₉Cl₂N₃O₂; NMR: 1.14 (t, 3H); 107 yl]-5-methyl-1H-pyrrole-2- 1.60 (br s, 2H); 2.17 (s, 3H); 2.62 (m, carboxamide 2H); 2.89 (m, 2H); 3.14 (m, 2H); 3.64 (m, 2H); 4.05 (m, 2H); 7.10 (d, 1H) 142 Trans(±)3,4-dichloro-5- MS (ES) MH⁺: 389, 391 for Intermediate methyl-N-[3-(morpholin-4- C₁₆H₂₂Cl₂N₄O₃ 111 ylcarbonyl)piperidin-4-yl]- 1H-pyrrole-2-carboxamide hydrochloride 143 Cis(±)3,4-dichloro-5-methyl- MS (ES) MH⁺: 389, 391 for Intermediate N-[3-(morpholin-4- C₁₆H₂₂Cl₂N₄O₃ 110 ylcarbonyl)piperidin-4-yl]- 1H-pyrrole-2-carboxamide hydrochloride 144 Cis(±)[(4-{[(3,4-dichloro-5- MS (ES)[(M + H)⁺]: 350, 352 for Intermediate methyl-1H-pyrrol-2- C₁₃H₁₇Cl₂N₃O₄ 112 yl)carbonyl]amino}piperidin- 3-yl)oxy]acetic acid

Intermediates 145-157

The following Intermediates were synthesized by an analogous method to Intermediate 59 from the starting materials (SM) given in the table below.

Int Compound Data SM 145 Cis(±)-ethyl 3-(benzyloxy)-4- [(tert- butoxycarbonyl)amino]piper- idine-1-carboxylate

MS (ES): 401 (M + Na) for C₂₀H₃₀N₂O₅; NMR (CDCl₃) δ: 1.25 (m, 3H); 1.43 (s, 9H); 1.65- 1.85 (m, 2H); 2.81 (m, 2H); 3.58 (s, 1H); 3.71 (m, 1H); 4.05-4.30 (m, 3H); 4.30 (m, 2H); 4.76 (t, 1H); 4.94 (m, 1H); 7.26-7.38 (m, 5H) cis(±)ethyl 4- [(tert- butoxycarbonyl)- amino]-3- hydroxypiperidine- 1-carboxylate (WO9412494) and Benzyl bromide 146 Cis(±)-ethyl 4-[(tert- NMR: (CDCl₃) 1.26 (t, 3H); 1.45 cis(±)ethyl 4- butoxycarbonyl)amino]-3- (s, 9H); 1.67 (m, 2H); 2.43 (t, [(tert- (prop-2-yn-1- 1H); 2.79 (m, 2H); 3.74 (m, 2H); butoxycarbonyl) yloxy)piperidine-1- 4.00-4.45 (m, 6H); 5.00 (s, 1H) amino]-3- carboxylate hydroxypiperidine- 1-carboxylate (WO9412494) and Propargyl bromide 147 Cis(±)-Ethyl (4- MS (ES) MH⁺: 337 for Intermediate 169 benzylamino)-3-(2- C₁₈H₂₈N₂O₄ methoxyethoxy)piperidine-1- carboxylate 148 Cis(±)-Ethyl 4-[(tert- MS (ES) M + Na: 383 for Intermediate 149 butoxycarbonyl)amino]-3-(2- C₁₇H₃₂N₂O₆ and methyl iodide methoxypropoxy)piperidine- 1-carboxylate 149 Cis(±)-Ethyl 4-[(tert- MS (ES) M + Na: 369 for Intermediate 150 butoxycarbonyl)amino]-3-(2- C₁₆H₃₀N₂O₆ (J. Org. Chem, 60, hydroxypropoxy)piperidine- 4922-4924, 1995) 1-carboxylate 150 Cis(±)-Ethyl 4-[(tert- butoxycarbony)amino]-3- (oxiran-2- ylmethoxy)piperidine-1- carboxylate

MS (ES) M + Na: 367 for C₁₆H₂₈N₂O₆ Intermediate 27 and m-CPBA 151 tert-butyl (Cis(±)-4- 1.39 (s, 9H), 1.54 (m, 2H), 1.93 Intermediate 170 (benzylamino)-3- (m, 1H), 2.80 (m, 2H), 3.20 (m, chloropiperidine-1- 1H), 3.75 (q, 2H), 4.06 (m, 1H), carboxylate 4.57 (s, 1H), 7.22-7.36 (m, 5H). 152 Cis(±)-ethyl 4- NMR (CDCl₃): 0.9 (d, 3H),1.2 ethyl 3-methyl-4- (benzylamino)-3- (t, 3H), 1.6 (m, 2H), 2.0 (m, 1H), oxopiperidine-1- methylpiperidine-1- 2.8 (m, 1H), 2.9-3.2 (m, 2H), 3.7 carboxylate carboxylate (m, 1H), 3.8 (s, 2H), 4.1 (m, 2H), (Ebnoether, A.; 7.2-7.4 (m, 5H). Niklaus, P.; Suess, R. Helvetica Chimica Acta (1969), 52(3), 629-38) 153 Cis(±)-ethyl (4- MS (ES) (MH⁺): 277 for Intermediate 164 (benzylamino)-2- C₁₆H₂₄N₂O₂: methylpiperidine-1- NMR (d₆-DMSO): 1.25 (t, 3H), carboxylate 1.3 (d, 3H), 1.3-1.5 (m, 2H), 1.65 (s, broad, 2H), 1.8-2.0 (m, 2H), 3.2-3.4 (m, 2H), 3.8 (m, 1H), 4.1 (3, 3H) 154 Cis(±)-Ethyl 4- MS (ES) MH⁺: 333 for Intermediate 171 (benzylamino)-3- C₁₉H₂₈N₂O₃; NMR: 0.14 (m, 2H), (cyclopropylmethoxy)piper- 0.42 (m, 2H), 0.97 (m, 1H), 1.15 idine-1-carboxylate (t, 3H), 1.51 (m, 2H), 2.67 (m, 1H), 2.79-3.01 (m, 2H), 3.19 (m, 1H), 3.53 (m, 1H), 3.73 (m, 3H), 3.88-4.02 (m, 3H), 7.18-7.35 (m, 5H) 155 Cis(±)-ethyl 4-[(tert- butoxycarbonyl)amino]-3- (1,3-thiazol-2- ylmethoxy)piperidine-1- carboxylate

MS (ES) MH⁺: 386 for C₁₇H₂₇N₃O₅S; NMR (CDCl₃): 1.24 (t, 3H), 1.42 (s, 9H), 1.63 (s, 1H), 1.69-1.81 (m, 2H), 2.82 (m, 2H), 3.67 (m, 2H), 4.10 (q, 2H), 4.40-4.60 (m, 1H), 4.76 (d, 1H), 4.94-5.25 (m, 2H), 7.31 (d, 1H), 7.74 (d, 1H) Intermediate 235 156 Cis(±)-Ethyl (4- MS (ES) MH⁺: 307 for Intermediate 172 (benzylamino)-3- C₁₇H₂₆N₂O₃; NMR: 1.08 (t, 3H); ethoxypiperidine-1- 1.15 (t, 3H); 1.50 (m, 2H); 1.75 carboxylate (br s, 1H); 2.65 (br s, 1H); 2.92 (m, 2H); 3.47 (br s, 1H); 3.55 (m, 1H); 3.71 (m, 3H); 3.88 (br s, 1H); 3.98-4.05 (m, 2H); 7.18- 7.34 (m 5H) 157 Cis(±)-ethyl 4- MS (ES) MH⁺: 293 for Intermediate 168 (benzylamino)-3- C₁₆H₂₄N₂O₃. NMR: 1.16 (t, 3H), methoxypiperidine-1- 1.50 (m, 2H), 1.89 (s, 2H), 2.66 carboxylate (m, 1H), 2.89 (dd, 2H), 3.26 (s, 3H), 3.67-3.83 (m, 3H), 3.99 (m, 3H), 7.18-7.37 (m, 5H)

Intermediates 158-167

The following Intermediates were synthesized by an analogous method to Intermediate 28 or Intermediate 59 from the starting materials (SM) given in the table below.

Int Compound Data SM 158 Cis(±)-ethyl 4-amino-3- MS (ESP): 279 (M + H) for Intermediate 145 (benzyloxy)piperidine-1- C₁₅H₂₂N₂O₃ carboxylate 160 Cis(±)-Ethyl 4-amino-3-(2- methoxypropoxy)piperidine- 1-carboxylate hydrochloride

MS (ES) MH⁺: 261 for C₁₂H₂₄N₂O₄ Intermediate 148 161 Cis(±)-Ethyl 4-amino-3-(2- MS (ES) MH⁺: 247 for Intermediate 149 hydroxypropoxy)piperidine- C₁₁H₂₂N₂O₄ 1-carboxylate hydrochloride 162 tert-butyl Cis(±)-4-amino-3- 1.39 (s, 9H), 1.45 (m, 1H), 1.58 Intermediate 151 chloropiperidine-1- (m, 2H), 2.95 (m, 1H), 3.31 (m, carboxylate 1H), 3.82 (m, 1H), 4.03 (m, 1H), 4.26 (m, 1H) 163 ethyl Cis(±)-4-amino-3- NMR (CDCl₃): 0.9 (d, 3H), 1.2 Intermediate 152 methylpiperidine-1- (t, 3H), 1.5 (m, 2H), 1.6 (m, 1H), carboxylate 2.2 (s, broad, 2H), 3.0 (m, 1H), 3.2 (m, 2H), 3.4 (m, 1H), 4.0-4.2 (m, 2H) 164 Cis(±)-ethyl (4-amino-2- NMR: 1.25 (t, 3H), 1.3 (d, 3H), ethyl 2-methyl-4- methylpiperidine-1- 1.3-1.5 (m, 2H), 1.65 (s, broad, oxopiperidine-1- carboxylate 2H), 1.8-2.0 (m, 2H), 3.2-3.4 (m, carboxylate (EP 2H), 3.9 (m, 1H), 4.1 (3, 3H) 121972 A2) 165 Cis(±)-Ethyl 4-amino-3- (cyclopropylmethoxy)piper- idine-1-carboxylate

MS (ES) MH⁺: 243 for C₁₂H₂₂N₂O₃; NMR (CDCl₃): 0.19 (m, 2H), 0.49 (m, 2H), 1.05 (m, 1H), 1.24 (t, 3H), 1.65-1.84 (m, 2H), 2.93 (d, 2H), 3.09 (m, 1H), 3.25-3.44 (m, 2H), 3.52 (bs, 1H), 3.85-4.21 (m, 6H) Intermediate 154 166 Cis(±)-ethyl 4-amino-3-(1,3- MS (ES) MH⁺: 286 for Intermediate 155 thiazol-2- C₁₂H₁₉N₃O₃S; NMR (DMSO): ylmethoxy)piperidine-1- 1.00 (t, 1.8H), 1.15 (t, 1.2H), 1.70 carboxylate (m, 2H), 2.79-3.03 (m, 2H), 3.44 (m, 1H), 3.74-4.02 (m, 4H), 4.29 (m, 1H), 4.91 (t, 2H), 7.25 (bs, 1H), 7.77 (dd, 2H), 8.34 (s, 1H) 167 1-tert-butyl 3-methyl-4- MS (GC-EI)[(M)⁺]: 258 for Intermediate 237 aminopiperidine-1,3- C₁₂H₂₂N₂O₄ dicarboxylate

Intermediate 168 ethyl 3-methoxy-4-oxopiperidine-1-carboxylate

To a stirred solution of the methoxyketal (Intermediate 173, 55.15 g, 223 mmol, crude) in dry THF (30 mL), at room temperature and under ambient atmosphere, was added an aqueous solution of H₂SO₄ (5%, v/v, 190 mL). Temperature was increased to 60° C.; the reaction was stirred at this temperature. Complete conversion was suggested after 2 hours by TLC (50% ethyl acetate in hexanes; Hanessian's stain; Rf˜0.43). The reaction mixture was allowed to come to room temperature. THF was removed under vacuum. To the aqueous solution was added solid sodium bicarbonate until basic, and solid sodium chloride until saturated, with the addition of more water necessary. Crude product was extracted with methylene chloride (3×300 mL); the organic layers were combined, dried over magnesium sulfate, and concentrated. The crude material was used without further purification; yield was assumed quantitative.

MS (ESI) M: 201 for C₉H₁₅NO₄. ¹H NMR (CDCl₃): 1.28 (t, 3H), 2.38-2.60 (m, 2H), 3.30-3.41 (m, 2H), 3.45 (s, 3H), 3.69 (m, 1H), 4.05 (m, 2H), 4.17 (q, 2H).

Intermediates 169-172

The following Intermediates were synthesized by an analogous method to Intermediate 168 from the starting materials (SM) given in the table below.

Int Compound Data SM 169 Ethyl 3-(2-methoxyethoxy)-4- MS (ES) MH⁺: 246 for Intermediate 174 oxopiperidine-1-carboxylate C₁₁H₁₉NO₅ 170 tert-butyl 3-chloro-4- oxopiperidine-1-carboxylate

1.30 (m, 1H), 1.34 (s, 9H), 2.45 (t, 2H), 3.34 (m, 1H), 3.17 (m, 1H), 4.10 (m, 1H), 4.66 (m, 1H) J. Org. Chem., 1994, 59, 6955- 6964. 171 Ethyl 3-(cyclopropylmethoxy)- MS (ES) MH⁺: 242 for Intermediate 255 4-oxopiperidine-1-carboxylate C₁₂H₁₉NO₄; NMR (CDCl₃): and 0.21 (m, 2H), 0.53 (m, 2H), cyclopropylmethyl 1.07 (m, 1H), 1.28 (t, 3H), bromide 2.37-2.58 (m, 2H), 3.32-3.51 (m, 4H), 3.85 (bs, 1H), 4.04- 4.41 (m, 4H) 172 Ethyl 3-ethoxy-4- MS (ES) NMa⁺: 238 for Intermediate 175 oxopiperidine-1-carboxylate C₁₀H₁₇NO₄—Na adduct; NMR: 1.09 (t, 3H); 1.20 (t, 3H); 2.31 (m, 1H); 3.12 (br s, 1H); 3.45 (m, 1H); 3.59 (m, 1H); 3.94 (m, 2H); 4.03-4.11 (m, 4H).

Intermediate 173 ethyl 3,4,4-trimethoxypiperidine-1-carboxylate

To a stirred solution of sodium hydride (6.96 g, 290 mmol) in dry THF (100 mL), at 0° C. and under an atmosphere of N₂, was added a solution of the hydroxyketal (Intermediate 255, 223 mmol) in THF (125 mL) over approximately 30 minutes, via addition funnel. The resulting solution was stirred at 0° C. under an atmosphere of N₂ for approximately 15 minutes; to it was then added methyl iodide (18.0 mL, 41.0 g, 290 mmol) portionwise, via syringe, over approximately 5 minutes. The reaction was stirred overnight under an atmosphere of N₂, gradually reaching room temperature. Complete conversion was suggested by TLC (50% ethyl acetate in hexanes; Hanessian's stain; Rf˜0.57) in the morning. The reaction was quenched with a small volume of water, then concentrated under vacuum. To the residue was added approximately 50 mL of water; from this mixture was extracted the crude product with ethyl acetate (3×150 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated. The crude material was used without further purification; yield was assumed quantitative.

MS (ESI) M: 247 for C₁₁H₂₁NO₅. ¹H NMR (CDCl₃): 1.24 (t, 3H), 1.72-1.83 (m, 2H), 2.82 (m, 2H), 2.98 (t, 1H), 3.20 (s, 3H), 3.21 (s, 3H), 3.41 (s, 3H), 4.10 (q, 2H), 4.20-4.37 (m, 2H).

Intermediates 174-175

The following Intermediates were synthesized by an analogous method to Intermediate 173 from the starting materials (SM) given in the table below.

Int Compound Data SM 174 Ethyl 4,4-dimethoxy-3- NMR (CDCl₃): 1.23 (t, 3H), Intermediate 255 and 1- (2- 1.73-1.85 (m, 2H), 2.75-2.88 bromo-2-methoxyethane methoxyethoxy)piper- (m, 1H), 2.93-3.10 (m, 1H), idine-1-carboxylate 3.19 (s, 3H), 3.23 (s, 3H), 3.34 (s, 3H), 3.40-3.60 (m, 4H), 3.68-3.80 (m, 2H), 4.11 (q, 2H), 3.98-4.30 (m, 1H) 175 Ethyl 3-ethoxy-4,4- dimethoxypiperidine-1- carboxylate

MS (ES) MNa⁺: 284 for C₁₂H₂₃NO₅—Na adduct; NMR: 1.07 (t, 3H); 1.15 (t, 3H); 1.52 (m, 1H); 1.66 (m, 1H); 3.08 (s, 3H); 3.10 (s, 3H); 3.59 (m, 1H); 3.81 (m, 2H); 3.96-4.07 (m, 4H); 4.12 (m, 1H) Intermediate 255 and ethyl iodide

Intermediate 176 Ethyl 2-oxobutanoate

Diethyl oxalate (10 g; 68 mmol) was dissolved in Et₂O (100 ml) and cooled to −78 C. Ethyl magnesium bromide (1.0 M in THF; 72 ml; 71.8 mmol; 1.05 equiv.) was added slowly via syringe. The dry ice/acetone bath was allowed to melt and warm to 10 C. Monitored the reaction by ¹H NMR. The reaction was cooled to 0 C and quenched with saturated NH₄Cl. Dilute with H₂O and separate phases. The organic layer was dried over Na₂SO₄, filtered and concentrated. Isolation gave 7.6 g of a crude yellow oil in 86% yield. No further purification.

Intermediate 177 Ethyl 3-bromo-2-oxobutanoate

CuBr₂ (39.3 g; 176 mmol; 3 equiv.) was suspended in EtOAc (160 ml). A CHCl₃ solution containing ethyl 2-oxobutanoate (Intermediate 176, 7.6 g; 58.7 mmol) was added dropwise. The suspension was then heated to reflux for 6 hours and monitored by ¹H NMR. The solids were filtered through a pad of Celite and the mother liquor was concentrated. The crude oil was passed through a short plug of silica gel and eluted with a 1:1 mixture of EtOAc/hexanes. The yellow band was collected and concentrated to give 12.2 g of product. No further purification.

Intermediate 178 Ethyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate

Ethyl 3-bromo-2-oxobutanoate (Intermediate 177, 12.2 g; 58.7 mmol) and thiourea (4.46 g; 76.1; 58.7 mmol) were combined and heated to reflux. The solution was allowed to cool to room temperature and stir for 12 hours. The reaction was monitored by LC/MS. The base was precipitated with 20% NH₄OH (10 ml) and then redissolved with 1N HCl (100 ml) and then finally reprecipitated with 20% NH₄OH. The precipitate was collected and washed with H₂O. The crude product was then crystallized from 9:1 ethanol/water to give 5.95 g of product in 55% yield. MS (ES) MH⁺: 187 for C₇H₁₀N₂O₂S.

Intermediate 179 Ethyl 2-chloro-5-methyl-1,3-thiazole-4-carboxylate

Ethyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (Intermediate 178, 3 g; 16.1 mmol) and anhydrous CuCl₂ (3.25 g; 24.2 mmol; 1.5 equiv.) were combined in dry acetonitrile (28 ml). t-butyl nitrite (90% tech; 2.77 g; 24.2 mmol; 1.5 equiv.) was added dropwise. The suspension was stirred at room temperature for 12 hours and monitored by LC/MS. The acetonitrile was removed in vacou and the solid was redissolved in CHCl₃ and H₂O. The aqueous layer was acidified with 2N HCl and the phases were separated. Back extracted the aqueous with CHCl₃. The organic extracts were combined, dried over Na₂SO₄ and decolorizing carbon for 1 hour. Filtered through a pad of Celite and concentrated to an oil. Isolation gave 2.62 g of the title compound in 80% yield. The compound can be further purified via flash column chromatography and crystallization. MS (ES) MH⁺: 206, 208 for C₇H₈ClNO₂S.

Intermediate 180 Ethyl 5-(bromomethyl)-2-chloro-1,3-thiazole-4-carboxylate

Ethyl 2-chloro-5-methyl-1,3-thiazole-4-carboxylate (Intermediate 179, 2.8 g; 13.6 mmol) was dissolved in CCl₄ (25 ml). NBS (2.3 g; 13 mmol) and AIBN (2.12 g; 13 mmol) were added in a single portion and the resultant reaction mixture was heated to reflux for 24 hours. Additional NBS (690 mg; 0.3 equiv.) and AIBN (636 mg; 0.3 mmol) were added to push the reaction to completion. Continued to heat for another 4 hours. Cooled to room temperature, filtered and concentrated the mother liquor. Redissolved in minimal DMSO (7 ml) and purified by Gilson HPLC (5-95% ACN/0.1% TFA; run time=35 min). Isolated 1.15 g of desired product in 29% yield MS (ES) MH⁺: 284, 286, 288 for C₇H₇BrClNO₂S.

Intermediate 181 Ethyl 2-chloro-5-formyl-1,3-thiazole-4-carboxylate

Ethyl 5-(bromomethyl)-2-chloro-1,3-thiazole-4-carboxylate (Intermediate 180, 920 mg; 3.2 mmol) was dissolved in acetonitrile dried over molecular sieves. The solution was cooled to 0 C and NMO (570 mg; 1.5 equiv.) was added in a single portion. The reaction was monitored by LC/MS. An additional 1.5 equivalents of NMO was added in two portions over two hours. The reaction was concentrated to a solid residue, redissolved in EtOAc and washed with H₂O. Dried the organic over Na₂SO₄, filtered and concentrated. No further purification. MS (ES) MH⁺: 220, 222 for C₇H₆ClNO₃S.

Intermediate 182 tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate

Chlorotrimethylsilane (5.6 ml, 44 mmol) was added slowly to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (commercial, 8 g, 40 mmol), triethylamine (12.3 ml, 88 mmol) and DMF (40 ml) at room temperature. The resultant solution was heated to 75° C. and stirred overnight under nitrogen. The reaction mixture was cooled to room temperature and then in an ice bath. Cold hexane (250 ml) was added slowly to the reaction mixture followed by cold (saturated) aqueous sodium bicarbonate (50 ml). The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude silyl enolether was dissolved in THF (15 ml) and cooled to 0° C. N-Bromosuccinimide (7.1 g, 40 mmol) was dissolved in THF (120 ml) and added slowly (45 min.) to the reaction mixture. The resultant mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexanes/ethyl acetate, 5:1) to provide the title compound as a white solid (11 g).

MS (ESP): 222.1 (M-tBu) for C₁₀H₁₆BrNO₃.

¹H NMR (300 MHz, DMSO-d₆) δ: 1.25 (s, 9H); 2.30 (m, 1H); 2.55 (m, 1H); 3.42-3.80 (m, 3H); 3.93 (m, 1H); 4.60 (m, 1H).

Intermediate 183 tert-Butyl 3-(methylthio)-4-oxopiperidine-1-carboxylate

Sodium thiomethoxide (805 mg, 11.5 mmol) was added to a solution of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (Intermediate 182, 3.20 g, 11.5 mmol) and THF (15 ml) at 0° C. The resultant mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched with water (15 ml) and diluted with ethyl acetate (150 ml). The organic phase was separated and washed with brine. The combined aqueous phase was back extracted with ethyl acetate (50 ml). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexanes/ethyl acetate, 7:1) to provide the title compound (2.4 g).

MS (ESP): 190.2 (M-tBu) for C₁₁H₁₉NO₃S.

¹H NMR (300 MHz, CDCl₃) δ: 1.43 (s, 9H); 2.02 (s, 3H); 2.23 (dt, 1H); 2.95 (m, 1H); 3.20-3.40 (m, 2H); 3.65 (m, 1H); 3.90-4.20 (m, 2H).

Intermediate 184 Cis(±)-tert-butyl-4-amino-3-(methylthio)piperidine-1-carboxylate

Sodium cyanoborohydride (344 mg, 5.48 mmol) was added to a solution of tert-butyl 3-(methylthio)-4-oxopiperidine-1-carboxylate (Intermediate 183, 1.07 g, 4.40 mmol), ammonium acetate (3.24 g, 42 mmol) and methanol (15 ml). The resultant mixture was stirred for 4 h. The reaction was quenched by addition of 1N HCl (3 ml). Aqueous sodium bicarbonate (saturated, 50 ml) was added slowly to the reaction mixture followed by extraction with ethyl acetate (3×75 ml). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield the crude amine

MS (ESP): 247.3 (M+H) for C₁₁H₂₂N₂O₂S.

Intermediate 185 Trans(±)tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate

The title compound was prepared as described in Marquis R. W. et al. J. Med. Chem. 1998, 41,3563-3567 and/or WO 9805336. MS (ES) MH⁺: 217 for C₁₀H₂₀N₂O₃; NMR: 1.45 (s, 9H), 1.80 (m, 1H), 1.95 (m, 1H), 2.21 (m, 1H), 2.62 (m, 1H), 2.75 (m, 1H), 3.28 (m, 1H), 3.47 (m, 1H), 3.81 (m, 1H), 4.11 (m, 1H), 4.28 (m, 1H), 8.20 (m, 1H).

Intermediate 186 Ethyl 3-chloro-5-methyl-1H-pyrrole-2-carboxylate

The compound was prepared by the procedure described for Intermediate 2.

MS (ESP): 188 (MH⁺) for C₈H₁₀ClNO₂.

¹H-NMR (CDCl₃) δ: 1.37 (t, 3H); 2.26 (s, 3H); 4.32 (q, 2H); 5.96 (s, 1H); 8.81 (br, 1H).

Intermediate 187 Ethyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate

The compound was prepared by the procedure described for Intermediate 2.

MS (ESP): 234 (MH⁺) for C₈H₁₀BrNO₂.

¹H-NMR δ: 1.27 (t, 3H); 2.17 (s, 3H); 4.22 (q, 2H); 6.74 (s, 1H); 12.10 (s, br, 1H).

Intermediate 188 4 Ethyl 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylate

Ethyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 187, 2.87 g, 12.4 mmol) was dissolved in dry DMF (30 ml), N-chlorosuccinimide (1.66 g, 12.4 mmol) was added and resulting mixture was stirred at room temperature over night, more N-chlorosuccinimide (0.83 g, 6.2 mmol) was added and the reaction temperature was increased to 35° C., stirred for 4 hours. The mixture was poured into cold sodium hydroxide aqueous solution (2M) (50 ml), extracted with diethyl ether (2×50 ml). The organic phase was then washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and purified by column chromatography(hexanes/ethyl acetate, gradient) to give the desired product as a white crystal. (1.2 g).

MS (ESP): 268 (MH¹) for C₈H₉BrClNO₂.

¹H-NMR (CDCl₃) δ: 1.38 (t, 3H); 2.30 (s, 3H); 4.34 (q, 2H); 9.0 (br, 1H).

Intermediate 189 ethyl 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylate

N-Chlorosuccinimide (1.77 g, 13.25 mmol) was added to a solution of ethyl 3,5-dimethyl-2-pyrrole carboxylate (2.11 g, 12.62 mmol) in chloroform (45 mL). The reaction mixture was stirred at room temperature for 24 h and then poured into 2 N NaOH. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. The crude solid was dissolved in hot MeOH, cooled to room temperature, and the precipitate was collected by filtration (493 mg, 19%). MS (ES) MH⁺: 174 for C₉H₁₂ClNO₂.

Intermediate 190 ethyl 4-chloro-3-[(E)-(methoxyimino)methyl]-5-methyl-1H-pyrrole-2-carboxylate

A solution of Intermediate 191 (300 mg, 1.39 mmol) in MeOH (5 mL) and pyridine (1.5 mL) with methylamine hydrochloride (255 mg, 3.06 mmol) was heated to 60° C. overnight. The reaction was cooled to room temperature and then partitioned between methylene chloride and 10% HCl. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an off-white solid.

MS (ES) MH⁺: 245 for C₁₀H₁₃ClN₂O₃;

NMR (DMSO-d₆): 1.29 (t, 3H), 2.36 (s, 3H), 3.83 (s, 3H), 4.27 (q, 2H), 8.03 (s, 1H), 12.31 (s, 1H).

Intermediate 191 ethyl 4-chloro-3-formyl-5-methyl-1H-pyrrole-2-carboxylate

POCl₃ in 1,2-dichloroethane (14 mL) was slowly added to a solution of DMF (4.37 mL, 59.79 mmol) in 1,2-dichloroethane (10 mL). The reaction mixture was stirred for 15 min and then Intermediate 7 (2.04 g, 10.87 mmol) was added. The reaction mixture was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was treated with sodium acetate (10 g) in water (25 mL) and stirred for 1 h. The mixture was extracted with methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 2:1 hexanes/ethyl acetate) gave the desired compound (720 mg).

MS (ES) MH⁺: 216 for C₉H₁₀ClNO₃.

Intermediate 192 ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate

Bromine (0.56 ml, 11 mmol) was added to a solution of 1 g (5.3 mmol) of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7) and 0.8 ml (5.7 mmol) Et₃N in CH₂Cl₂. After stirring at room temperature for 2 h, aqueous NaHSO₃ was added and the CH₂Cl₂ was removed and the aqueous residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying (MgSO₄) and removal of solvent gave 1.5 g of product as a solid. MS (ES) (MH⁺): 240 for C₈H₉BrClNO₂; NMR (d₆-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.2 (q, 2H), 12.3 (s, 1H).

Intermediate 193 ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate

Nitrogen gas was bubbled through a mixture of 1.4 g (5.25 mmol) of ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 192), 470 g (4 mol) Zn(CN)₂, 250 mg (0.26 mmol) Pd₂(dba)₃ and 302 mg (0.26 mmol) dppf in 15 ml DMF for 15 min. The mixture was heated at 130° C. for 1 h. Additional Zn(CN)₂ (1 g), Pd₂(dba)₃ (500 mg) and dppf (604 mg) were added. After bubbling through N₂ for 15 min and heating at 130° C. for 2 h, additional Zn(CN)₂ (0.5 g), Pd₂(dba)₃ (250 mg) and dppf (302 mg) were added. Heating was continued at 130° C. for 2h. Solvent was removed and the residue was partitioned between EtOAc and water. The EtOAc was separated and washed with brine. Combined aqueous layers were extracted again with EtOAc, which was washed with brine. Combined EtOAc extracts were dried (MgSO₄) and concentrated. The residue was purified by silica gel chromatography (100% CH₂Cl₂ followed by gradient elution to 5% MeOH in CH₂Cl₂) to afford 750 mg of product as a solid. MS (ES) (MH⁺): 213 for C₉H₉ClN₂O₂; NMR (d₆-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.3 (q, 2H), 13.1 (s, 1H).

Intermediate 194 ethyl 3,5-dichloro-4-methyl-1H-pyrrole-2-carboxylate

Et₃N (5.5 ml, 39 mmol) was added slowly to a solution of 2.0 g (13 mmol) of ethyl 4-methyl-1H-pyrrole-2-carboxylate and 3.1 ml SO₂Cl₂ in 30 ml CH₂Cl₂ cooled in an ice water bath. The mixture was warmed to room temperature with stirring overnight. After treatment with aqueous NaHSO₃, the CH₂Cl₂ was removed and the aqueous residue was diluted with water and extracted twice with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO₄) and concentrated. The solid residue was twice recrystallized from 50% aqueous EtOH to afford 1.38 g of product as a white solid. MS (ES) (M−H⁻): 222 for C₈H₉Cl₂NO₂; NMR (d₆-DMSO): 1.3 (t, 3H), 1.9 (s, 3H), 4.25 (q, 2H), 12.8 (s, 1H).

Intermediate 195 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylic acid

Prepared using the procedure described for Intermediate 1 using Intermediate 189 as the starting material.

MS (ES) MH⁺: 174 for C₇H₈ClNO₂.

Intermediate 196 3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid

Prepared using the procedure described for Intermediate 1 using Intermediate 186 as the starting material.

MS (ESP): 160 (MH⁺) for C₆H₆ClNO₂.

¹H-NMR (CDCl₃) δ: 2.29 (s, 3H); 6.02 (s, 1H); 8.83 (br, 1H).

Intermediate 197 4-bromo-5-methyl-1H-pyrrole-2-carboxylic acid

Prepared by the procedure described for Intermediate 1 using Intermediate 187 as the starting material.

MS (ESP): 206 (MH⁺) for C₆H₆BrNO₂.

NMR (CDCl₃) δ: 2.31 (s, 3H); 6.97 (s, 1H); 9.08 (s, br, 1H).

Intermediate 198 4-bromo-3-chloro-5-methyl-1H-pyrrole-2-carboxylic acid

Prepared using the procedure described for Intermediate 1 and Intermediate 188. MS (ESP): 240 (MH⁺) for C₆H₅BrClNO₂.

Intermediate 199 4-chloro-3-[(E)-(methoxyimino)methyl]-5-methyl-1H-pyrrole-2-carboxylic acid

Synthesized as described for Intermediate 1 from Intermediate 190.

MS (ES) MH⁺: 217 for C₉H₉ClN₂O₃.

Intermediate 200 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid

A solution of 670 mg (3.2 mmol) of ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 193) and 3.2 ml (3.2 mmol) 1N NaOH in 20 ml MeOH was heated at 100° C. in a microwave reactor for 2 h. The mixture was diluted with water and extracted with EtOAc. The EtOAc was washed with 1N NaOH. The combined aqueous layers were acidified with concentrated HCl and extracted 2 times with EtOAc, each extract being washed with brine. Drying (MgSO₄) and removal of solvent gave 535 mg of product as a solid. MS (ES) (M−H⁻): 183 for C₇H₅ClN₂O₂; NMR (d₆-DMSO): 2.2 (s, 3H), 12.9 (s, 1H), 13.3 (s, 1H).

Intermediate 201 3,5-dichloro-4-methyl-1H-pyrrole-2-carboxylic acid

A solution of 1.1 gm (4.95 mmol) of ethyl 3,5-dichloro-4-methyl-1H-pyrrole-2-carboxylate (Intermediate 194) and 1.7 g (9.9 mmol) of Ba(OH)₂ in 50 ml 1:1 EtOH—H₂O was heated at 85° C. for 9 h. The mixture was diluted with water, acidified with 20 ml 1N HCl and extracted 3 times with ether. The ether was washed with water, dried (MgSO₄) and concentrated to give 1.0 g of product as a solid. MS (ES) (M−H⁻): 194 for C₆H₅Cl₂NO₂; NMR (d₆-DMSO): 1.9 (s, 3H), 12.7 (s, 1H), 12.8 (s, 1H).

Intermediate 202 3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl chloride

A solution of 10.4 g (54 mmol) of 3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 1) in 100 ml SOCl₂ was heated at reflux for 30 min. Solvent was removed to afford product. NMR (CDCl₃): 2.3 (s, 1H), 8.8 (s, 1H).

Intermediate 203 2,2,2-trichloro-1-(4,5-dichloro-1H-pyrrol-2-yl)ethanone

To a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1.00 g, 47.06 mmol) in dichloromethane (8 mL), sulfuryl chloride (1.60 mL, 0.188 mol) was added slowly at room temperature. The reaction was stirred overnight and quenched with water and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate, water and brine. Then it was dried over magnesium sulfate and concentrated to give the desired product as a white solid (0.90 g).

MS (ES) M⁻: 279 for C₆H₂Cl₅O.

Intermediate 204 ethyl 2-bromo[1,3]thiazolo[4,5-b]pyridine-7-carboxylate

To a 0° C. mixture of CuBr₂ (229 mg, 1.02 mmol) in acetonitrile (3 mL) was slowly added t-Butyl nitrite (0.15 mL, 1.28 mmol). The reaction mixture was stirred for 15 min and then added Intermediate 205 (250 mg, 0.85 mmol). The reaction mixture was stirred for 2 h, partitioned between diethyl ether and water, and filtered through diatomaceous earth. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate) gave the desired product (38 mg, 16%).

MS (ES) MH⁺: 174 for C₉H₇BrN₂O₂S.

Intermediate 205 ethyl 2-amino[1,3]thiazolo[4,5-b]pyridine-7-carboxylate

To a solution of Intermediate 206 (944 mg, 4.20 mmol) in acetic acid (12 mL) was added benzyltrimethyl ammonium tribromide (1.67 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 h and the solid that formed was collected by filtration to provide the desired compound as the acetic acid salt (1.20 g).

MS (ES) MH⁺: 224 for C₉H₉N₃O₂S.

Intermediate 206 ethyl 2-[(aminocarbonothioyl)amino]isonicotinate

A solution of Intermediate 207 (2.10 g, 6.38 mmol) in ethanol (20 mL) and potassium carbonate (882 mg, 6.38 mmol) was heated to 80° C. for 2 h. The reaction mixture was cooled to room temperature and the solid that formed was collected by filtration to give the desired compound.

MS (ES) MH⁺: 226 for C₉H₁₁N₃O₂S;

NMR (DMSO-d₆): 1.17 (t, 3H), 4.18 (q, 2H), 7.29 (m, 1H), 7.59 (s, 1H), 8.25 (m, 1H), 8.87 (s, 1H), 10.24 (s, 1H), 10.63 (s, 1H).

Intermediate 207 ethyl 2-{[(benzoylamino)carbonothioyl]amino} isonicotinate

To a 0° C. solution of benzyl isothiocyanate (1.25 mL, 9.27 mmol) in acetone (15 mL) was slowly added ethyl 2-aminoisonicotinate (1.4 g, 8.43 mmol). The reaction mixture was stirred for 1 h and then poured onto ice. The solid that formed was collected by filtration and washed with water to give the desired product (2.10 g).

MS (ES) MH⁺: 330 for C₁₆H₁₅N₃O₃S.

Intermediate 208 2-chloro-5-nitroisonicotinic acid

A solution of 13.7 g (46 mmol) of Na₂Cr₂O₃ in 100 ml concentrated H₂SO₄ was added slowly to a solution of 3.0 g (17.4 mmol) of 2-chloro-4-methyl-5-nitropyridine dissolved in 100 ml concentrated H₂SO₄ while cooling in ice water. Allowed to warm to room temperature and stir overnight. The solution was poured onto 600 ml ice and extracted twice with EtOAc, each extract being washed with brine. The combined organic extracts were dried (MgSO₄) and concentrated to afford product as a gummy oil. MS (ES) MH⁺: 203 for C₆H₃ClN₂O₄.

Intermediate 209 ethyl 2-amino-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate

A solution of 5.0 g (37 mmol) of 3-chlorofuran-2,4(3H,5H) -dione and 3.3 g (43 mmol) of thiourea in 50 ml EtOH was heated at reflux for 4 h. Solvent was removed and the residue was dissolved in water with 1N HCl added. The aqueous solution was basified with aqueous Na₂CO₃. Thick solids that formed were filtered, rinsed with water and dried in vacuo. NMR: 1.2 (t, 3H), 4.2 (q, 2H), 4.6 (s, 2H), 4.9 (s, broad, 1H), 7.8 (s, 2H).

Intermediate 210 ethyl 2-amino-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole-5-carboxylate

To a solution of 2.0 g (9.8 mmol) of ethyl 2-amino-4-(hydroxymethyl) -1,3-thiazole-5-carboxylate (Intermediate 209) and 1.3 g (19.4 mmol) of imidazole in 20 ml DMF was added 1.6 g (10.6 mmol) of t-butyldimethylsilyl chloride. After stirring for 2 h, solvent was removed and the residue was taken up in water. Insoluble solids were collected, ground up, washed with water and dried in vacuo to afford 2.95 g of product. MS (ES) (MH⁺): 317 for C₁₃H₂₄N₂O₃SSi; NMR (d₆-DMSO): 0.03 (s, 6H), 0.86 (s, 9H), 1.2 (t, 3H), 4.1 (q, 2H), 4.8 (s, 2H), 7.8 (s, 2H).

Intermediate 211 ethyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazole-5-carboxylate

t-Butylnitrite (1.8 ml (14 mmol) was added slowly to a mixture of 2.9 g (9.2 mmol) of ethyl 2-amino-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole-5-carboxylate (Intermediate 210) and 1.95 g (14 mmol) CuCl₂ in CH₃CN. After stirring at room temperature for 2 h, solvent was removed and the residue was taken up in EtOAc, which was washed 2 times with 1NHCl and once with brine. Drying (MgSO₄) and removal of solvent gave 2.95 g of product as an oil. NMR (CDCl₃): 0.1 (s, 6H), 0.9 (s, 9H), 1.35 (t, 3H), 4.3 (q, 2H), 5.0 (s, 2H).

Intermediate 212

The following Intermediate was synthesized by an analogous method to Intermediate 211 from the starting materials (SM) given in the table below

Int Compound Data SM 212 methyl 4-acetyl-2- NMR (CDCl₃): 2.6 (s, Intermediate 222 chloro-1,3-thiazole- 3H), 3.9 (s, 3H) 5-carboxylate

Intermediate 214 methyl 2-chloro-4-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carboxylate

A solution of 5.6 ml (11.2 mmol) 2N AlMe₃ in toluene was added to a dry ice-acetone bath of 1.14 g (5.2 mol) of methyl 4-acetyl-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 212) in 20 ml dry CH₂Cl₂. The mixture was allowed to warm to room temperature slowly before being quenched with MeOH. After stirring at room temperature overnight, the mixture was diluted with 1N HCl and stirred 15 min before being diluted with water and extracted twice with EtOAc. The EtOAc was washed with brine, dried (MgSO₄) and concentrated to give an oil that was purified by chromatography (50% hexanes in CH₂Cl₂ with gradient elution to 100% CH₂Cl₂) affording 720 mg of product as an oil. NMR (CDCl₃): 1.5 (s, 6H), 3.8 (s, 3H), 5.7 (s, broad, 1H).

Intermediate 215 ethyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate

A solution of 17.7 g (53 mmol) of ethyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 211) and 53 ml (53 mmol) of 1N HCl in dioxane was stirred at room temperature for 1 h. The mixture was extracted 3 times with EtOAc, which was dried (MgSO₄) and concentrated to give 11.3 g of an orange oil. Purification by silica gel chromatography affords a solid. NMR (CDCl₃): 1.2 (t, 3H), 3.1 (s, broad, 1H), 4.2 (q, 2H), 4.8 (s, 2H).

Intermediate 216 4-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazol-5-yl]carbonyl}morpholine

A solution of 2N Me₃Al in hexanes (0.91 ml, 1.82 mmol) was added slowly to a solution of 0.16 ml (1.8 mmol) of morpholine in 4 ml CH₂Cl₂. After stirring for 15 min, a solution of 0.5 g (1.5 mmol) of ethyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 218) in 4 ml CH₂Cl₂ was added. The solution was heated at 80° C. in a microwave reactor for 1 hour before pouring into dilute aqueous HCl. The mixture was extracted 3 times with CH₂Cl₂, which was washed with brine, dried (MgSO₄) and concentrated. The residue was purified by silica gel chromatography (100% CH₂Cl₂ followed by gradient elution to 30% EtOAc in CH₂Cl₂ to give 315 mg of product. MS (ES) (MH⁺): 377 for C₁₅H₂₅ClN₂O₃SSi; NMR (d₆-DMSO): 0.1 (s, 6H), 0.9 (s, 9H), 3.6 (m, 4H), 3.7 (m, 4H), 4.1 (q, 2H), 4.75 (s, 2H).

Intermediate 217

The following Intermediate was synthesized by an analogous method to Intermediate 216 from the starting materials (SM) given in the table below.

Int Compound Data SM 217 4-({[tert- NMR (d₆-DMSO): Intermediate 211 and butyl(dimethyl)silyl]oxy}methyl)- 0.04 (s, 6H), 0.8 (s, 9H), 1.6 (s, cumylamine 2-chloro-N-(1-methyl-1- 6H), 4.9 (s, 2H), 7.2 (7, phenylethyl)-1,3-thiazole-5- 1H), 7.3 (t, 2H), 7.4 (d, carboxamide 2H), 8.6 (s, 1H).

Intermediate 218 2-chloro-5-(morpholin-4-ylcarbonyl)-1,3-thiazole-4-carboxylic acid

A solution of 173 mg (1.7 mmol) CrO₃ in 1 ml of 4:1 water/H₂SO₄ was added to as solution of 310 mg (0.82 mmol) of 4-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazol-5-yl]carbonyl}morpholine (Intermediate 216) in 3 ml acetone cooled in an ice water bath. The mixture was stirred with warming room temperature over 90 min. A few drops of isopropanol were added, and the mixture was diluted with water and extracted 2 times with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO₄) and concentrated to give 190 mg of a white solid. MS (ES) (MH⁺): 277 for C₉H₉ClN₂O₄S; NMR (d₆-DMSO): 3.3 (m, 4H), 3.6 (m, 4H), 13.7 (s, 1H).

Intermediate 219

The following Intermediate was synthesized by an analogous method to Intermediate 218 from the starting materials (SM) given in the table below.

Int Compound Data SM 219 2-chloro-5-{[(1-methyl-1- MS (ES) (M − H⁻): Inter- phenylethyl)amino]carbonyl}-1,3- 323 for mediate thiazole-4-carboxylic acid C₁₄H₁₃ClN₂O₂S 217

Intermediate 220 ethyl 5-(aminocarbonyl)-2-chloro-1,3-thiazole-4-carboxylate

A solution of 210 mg of ethyl 2-chloro-5-{[(1-methyl-1-phenylethyl)amino]carbonyl}-1,3-thiazole-4-carboxylate (Intermediate 233) in 5 ml TFA was stirred at room temperature overnight. Solvent was removed and the residue was dissolved in 5 ml MeOH. Solvent was again removed and the residue was triturated with ether to give 57 mg of a white solid. NMR (d₆-DMSO): 1.3 (t, 3H), 4.3 (q, 2H), 8.2 (s, 1H), 8.8 (s, 1H).

Intermediate 221 methyl 2-chloro-4,4-dimethoxy-3-oxopentanoate

SO₂Cl₂ (2.2 ml, 27 mmol) was added slowly to a solution of 5.0 g (26 mmol) of methyl 4,4-dimethoxy-3-oxopentanoate in 30 ml CH₂Cl₂ cooled in an ice water bath. The solution was warmed to room temperature and stirred for 1 h. Solvent was removed and the residue was taken up in EtOAc, which was washed with water and brine. Drying (MgSO₄) and removal of solvent gave 6.1 g of an oil. NMR: (CDCl₃): 1.5 (s, 3H), 3.25 (2s, 6H), 4.8 (s, 3H), 5.3 (s, 1H).

Intermediate 222 methyl 4-acetyl-2-amino-1,3-thiazole-5-carboxylate

A solution of 4.37 g (19 mmol) methyl 2-chloro-4,4-dimethoxy-3-oxopentanoate (Intermediate 221) and 1.8 g (24 mmol) thiourea in 50 ml EtOH was heated at reflux for 3 h. Solvent was removed and the residue was dissolved in 1:1 acetone-5N HCl and the solution was heated at reflux for 4 h. Acetone was removed and the aqueous residue was neutralized with 50% NaOH and then basified with aqueous Na₂CO₃. Precipitated solids were filtered, washed with water and dried in vacuo. NMR (d₆-DMSO): 2.4 (s, 3H), 3.7 (s, 3H), 8.0 (s, 2H).

Intermediate 223 isopropyl 4-chloropyridine-2-carboxylate 1-oxide

A solution of 2.55 g (14 mmol) of isopropyl 4-chloropyridine-2-carboxylate (Intermediate 232) and 1.4 g (26 mmol) of m-CPBA in 30 ml CH₂Cl₂ was stirred at room temperature for 2 d. The mixture was quenched with aqueous NaHSO₃ and CH₂Cl₂ was removed. The aqueous residue was basified with aqueous Na₂CO₃, saturated with NaCl and extracted repeatedly with EtOAc. The EtOAc was dried (MgSO₄) and concentrated. The residue was taken up in ether and insoluble material was filtered off. The filtrate was concentrated and the residue was chromatographed on silica gel (100% CH₂Cl₂ with gradient elution to 100% EtOAc) to afford 2.1 g of product as an oil. NMR (d₆-DMSO): 1.3 (d, 6H), 5.3 (septet, 1H), 7.25 (m, 1H), 7.5 (d, 1H), 8.1 (d, 1H).

Intermediate 224 isopropyl 4-chloro-6-cyanopyridine-2-carboxylate

A solution of 200 mg (0.86 mmol) of isopropyl 4-chloropyridine-2-carboxylate 1-oxide (Intermediate 223), 0.14 ml (1 mmol) Et₃N and 0.36 ml (2.7 mmol) of trimethylsilylcyanide in 3 ml CH₃CN was heated at 90° C. overnight. The solution was diluted with EtOAc and washed with water and brine. Drying (MgSO₄) and removal of solvent gave an oil that was purified by chromatography on silica gel (100% CH₂Cl₂ followed by gradient elution to 10% EtOAc in CH₂Cl₂) to afford 130 mg of product as a white solid. MS (ES) (MH⁺): 224 for C₁₉H₉ClN₂O₂; NMR (d₆-DMSO): 1.35 (d, 6H), 5.2 (septet, 1H), 8.4 (s, 1H), 8.6 (s, 1H).

Intermediate 225 ethyl 2-chloro-5-formylisonicotinate

A solution of 51 ml (128 mmol) of 2.5 N n-butyllithium in hexanes was added slowly to a THF solution of 16 ml (95 mmol) of tetramethylpiperidine cooled in a dry ice-acetone bath. The solution was warmed to −30° C. and cooled to −60° C. before 5.0 g (32 mmol) of 6-chloronicotinic acid was added portion wise. The mixture was warmed to −25° C. and stirred for 30 min. It was then cooled to −70° C. and 10 ml (129 mmol) DMF was added quickly. After quenching with 1N HCl, the solution was warmed to room temperature. The pH was brought to about 4 with additional 1N HCl and the solution was continuously extracted with EtOAc overnight. The EtOAc was dried (MgSO₄) and concentrated. The residue was dissolved in 100 ml EtOH and 2 ml concentrated H₂SO₄ was added. The solution was heated at reflux for 24 h. The mixture was brought to about pH=4 with 50% NaOH and was extracted twice with ether. The ether was dried (MgSO₄) and concentrated to gave an oil that was chromatographed on silica gel (50% hexanes in CH₂Cl₂ with gradient elution to 100% CH₂Cl₂) to afford 1 g of product as an oil that slowly solidified. NMR (CDCl₃): 1.4 (t, 3H), 4.5 (q, 2H), 7.7 (s, 1H), 9.1 (s, 1H), 10.7 (s, 1H).

Intermediate 226 ethyl 2-chloro-5-nitroisonicotinate

A mixture of 2-chloro-5-nitroisonicotinic acid (Intermediate 208) and 16 ml triethylorthoacetate in 100 ml toluene was heated at reflux for 2 h. The mixture as stirred with 1N HCl for 30 min before being partitioned between EtOAc and water. The EtOAc was separated, washed with water and brine, dried (MgSO₄) and concentrated. Chromatographed on silica gel (100% hexanes with gradient elution to 100% CH₂Cl₂ to give product as an oil. MS (ES) (MH⁺): 231 for C₈H₇ClN₂O₄; NMR (d₆-DMSO): 1.3 (t, 3H), 4.4 (m, 2H), 8.1 (s, 1H), 9.2 (s, 1H).

Intermediates 227-233

The following compounds were prepared in a manner analogous to Intermediate 226 from the starting material (SM) indicated.

Int Compound Data SM 227 isopropyl 2-chloro-6- MS (ES) (MH⁺): 214 2-chloro-6-methylisonicotinate methylisonicotinate for C₁₀H₁₂ClNO₂; and trisopropylorthoformate NMR (d₆-DMSO): 1.3 (d, 6H), 2.55 (s, 3H), 5.2 (septet, 1H), 7.65 (s, 1H), 7.7 (s, 1H) 228 isopropyl 4- NMR (CDCl₃): 1.35 (d, 4-chloropyridine-2-carboxylate chloropyridine-2- 6H), 5.3 (septet, 1H), and trisopropylformate carboxylate 7.4 (dd, 1H), 8.05 (d, 1H), 8.6 (d, 1H) 229 isopropyl 4,5- NMR (CDCl₃): 1.35 (d, 4,5-dichloropyridine-2- dichloropyridine-2- 6H), 5.3 (septet, 1H), carboxylate (Graf, R. J. fuer carboxylate 8.1 (s, 1H), 8.7 (s, 1H) Prakt. Chem. (Leipzig) (1932), 133 36-50) and trisopropylorthoformate 230 isopropyl 2- fluoroisonicotinate

NMR (CDCl₃): 1.4 (d, 6H), 5.3 (septet, 3H), 7.5 (m, 1H), 7.7 (m, 1H), 8.35 (d, 1H) 2-fluoroisonicotinic acid and trisopropylorthoformate 231 ethyl 2-chloro-5- NMR: 1.3 (t, 3H), 3.3 Intermediate 218 and (morpholin-4-ylcarbonyl)- (m, 2H), 3.5 (m, 2H), triethylorthoacetate 1,3-thiazole-4-carboxylate 3.6 (m, 2H), 3.65 (m 2H), 4.3 (q, 2H) 232 isopropyl 4- NMR (CDCl₃): 1.35 (d, 4-chloropyridine-2-carboxylic chloropyridine-2- 6H), 5.3 (septet, 1H), acid and carboxylate 7.4 (dd, 1H), 8.05 (d, trisopropylorthoformate 1H), 8.6 (d, 1H) 233 ethyl 2-chloro-5-{[(1- MS (ES) (MH+⁻): 353 Intermediate 219 methyl-1- for C₁₆H₁₇ClN₂O₂S and triethylorthoacetate phenylethyl)amino]car- bonyl}-1,3-thiazole-4- carboxylate

Intermediate 234 1,3-thiazol-2-ylmethanol

To a stirred solution of commercially available 1,3-thiazole-2-carbaldehyde (5.36 g, 47 mmol) in dry methanol (100 mL), at 0° C. and under an atmosphere of N₂, was added sodium borohydride (2.15 g, 57 mmol) as a solid over approximately 20 minutes. The reaction was stirred for an hour at ambient temperature, under an atmosphere of N₂. Complete conversion was suggested by TLC (50% ethyl acetate in hexanes; Rf˜0.23). The reaction was concentrated under vacuum. To the residue was added 15 mL of an aqueous solution of ammonium chloride, and 15 mL of an aqueous solution of sodium chloride; from this mixture was extracted the crude product with ethyl acetate (4×50 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated. The crude material was used without further purification.

MS (ES) MH⁺: 116 for C₄H₅NOS. ¹H NMR (DMSO): 4.72 (d, 2H), 6.03 (t, 1H), 7.61 (d, 1H), 7.71 (d, 1H).

Intermediate 235 2-(bromomethyl)-1,3-thiazole

This compound was synthesized from Intermediate 234 above, using the procedure described in Tetrahedron 61 (2005), p. 137. The crude material was purified by column chromatography (silica gel, 15% ethyl acetate in hexanes). A pale orange liquid (57% yield) was obtained; this material decomposed rapidly, and was used immediately in the next step.

MS (ES) MH⁺: 179 for C₄H₄BrNS. ¹H NMR (CDCl₃): 4.75 (s, 2H), 7.37 (d, 1H), 7.74 (d, 1H).

Intermediate 236 Ethyl 2-chloro-4-methyl-1,3-thiazole-5-carboxylate

Synthesized according to the procedure described for Intermediate 17. MS (ES) MH⁺: 206, 208 for C₇H₈ClNO₂S; ¹H-NMR (300 MHz; DMSO-d₆) δ: 1.28 (t, 3H); 2.60 (s, 3H); 4.28 (q, 2H).

Intermediate 237 1-tert-butyl 3-methyl 4-hydroxy-5,6-dihydropyridine-1,3(2H)-dicarboxylate

Methyl 4-oxopiperidine-3-carboxylate hydrochloride (13.0 g) was suspended in anhydrous DCM (100 mL) under an argon atmosphere. DIEA (29.2 mL) was added slowly via syringe, producing a slightly cloudy solution. The reaction was cooled to 0° C., and di-tert-butyl dicarboxylate (16.1 g) was added, resulting in an exothermic reaction. The reaction mixture was left stirring overnight, slowly warming to room temperature. The reaction mixture was then concentrated in vacuo and partitioned between EtOAc (500 mL) and saturated aqueous NH₄Cl (350 mL). The EtOAc layer was washed with brine (125 mL), dried over anhydrous MgSO₄ and concentrated in vacuo, producing a yellow oil. The product was purified by silica gel chromatography (1-25% EtOAc in hexanes), producing the title compound as a clear, colourless oil (14.7 g, 85.1%). MS (ES)[(M−H)⁻]: 256 for C₁₂H₁₉NO₅; NMR (CDCl₃): 1.46 (s, 9H), 2.36 (t, 2H), 3.55 (t, 2H), 3.76 (s, 3H) 4.04 (s, 2H), 11.97 (s, 1H).

Intermediate 238 Ethyl 4-azido-3-hydroxypiperidine-1-carboxylate

Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (5.1 g) was dissolved in anhydrous DMF (20 mL) under an argon atmosphere, followed by the addition of 18-crown-6 (0.27 g) and sodium azide (2.89 g). The reaction was heated at 90° C. for twenty-three hours, then stirred overnight, slowly cooling to room temperature. The reaction was then added to deionised water (150 mL) to quench it, saturated with solid sodium chloride, and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with brine (100 mL), dried over anhydrous MgSO₄ and concentrated in vacuo, yielding the title compound (4.3 g, 100%). MS (GC-EI)[(M-N₂)⁺]: 186 for C₈H₁₄BrN₄O₃.

Intermediate 239 Ethyl 4-azido-3-(2-tert-butoxy-2-oxoethoxy)piperidine-1-carboxylate

Ethyl 4-azido-3-hydroxypiperidine-1-carboxylate (Intermediate 238, 1.71 g) was dissolved in anhydrous THF (15 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil) (0.42 g) was added as a shot, stirred for twenty minutes at 0° C., followed by the slow addition of tert-butyl bromo acetate (0.86 mL) via syringe, and stirred for an additional two hours at 0° C. The reaction was partitioned between EtOAc (250 mL) and saturated aqueous NaHCO₃ (200 mL), and the aqueous layer was washed with EtOAc (200 mL). The combined EtOAc layers were washed with brine (50 mL), dried over anhydrous MgSO₄ and concentrated in vacuo, yielding the title compound as a crude product (1.78 g, 103%). MS (GC-EI)[(M-N₂)⁺]: 300 for C₁₄H₂₄N₄O₅.

Intermediate 240 Ethyl 4-amino-3-(2-tert-butoxy-2-oxoethoxy)piperidine-1-carboxylate

Ethyl 4-azido-3-(2-tert-butoxy-2-oxoethoxy)piperidine-1-carboxylate (Intermediate 239, 1.75 g) was dissolved in THF (60 mL), followed by the addition of deionised water (5 mL) and PS-triphenylphosphine resin (10.6 g), and stirred at room temperature over the week-end. The reaction mixture was filtered, and the resin was rinsed repeatedly with MeOH and a 1:5 MeOH:DCM mixture, and the filtrate was concentrated in vacuo, yielding the title compound (1.20 g, 75%). MS (GC-EI)[(M)⁺]: 302 for C₁₄H₂₆N₂O₅.

Intermediate 241 Ethyl 4-bromo-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate

Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (10.17 g) was dissolved in anhydrous DCM (100 mL) under an argon atmosphere and cooled to 0° C. tert-Butyldimethylsilyl trifluoromethylsulfonate (10.2 mL) was added dropwise via syringe, followed by 2,6-lutidine (4.7 mL), also added dropwise via syringe. The reaction was stirred overnight, slowly warming to room temperature, then diluted with DCM (200 mL) and washed with saturated aqueous NaHCO₃ (150 mL), saturated aqueous NH₄Cl ((150 mL), brine (100 mL), dried over anhydrous MgSO₄ and concentrated in vacuo, yielding the title compound as a crude product (15.1 g, 102%). MS (GC-EI)[(M-C₄H₇)⁺]: 310, 312 for C₁₄H₂₈BrNO₃Si; NMR (CDCl₃): 0.10 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 1.24 (t, 3H), 1.87 (m, 1H), 2.34 (m, 1H), 2.84-3.40 (m, 2H), 3.69 (m, 2H), 3.93 (m, 2H), 4.13 (q, 2H).

Intermediate 242 Ethyl 4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate

The title compound was prepared in a manner analogous to (Intermediate 238) starting with ethyl 4-bromo-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate (Intermediate 241). MS (GC-EI)[(M-N₂)⁺]: 300 for C₁₄H₂₈N₄O₃Si.

Intermediate 243 Ethyl 4-amino-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate

The title compound was prepared in a manner analogous to (Intermediate 240) starting with ethyl 4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate (Intermediate 242. MS (GC-EI)[(M)⁺]: 302 for C₁₄H₃₀N₂O₃Si.

Intermediate 244 3,4-dichloro-N-(3-hydroxypiperidin-4-yl)-5-methyl-1H-pyrrole-2-carboxamide

Ethyl 3-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 114, 0.805 g) was dissolved in a mixture of MeOH (10 mL) and 1,4-dioxane (15 mL), to which was added 1N NaOH (10 mL) and heated to reflux for twenty-four hours. An additional 5 mL of 1N NaOH was added, with 5 mL of 1,4-dioxane, and the reaction was heated for an additional forty-two hours, then cooled to 0° C. and acidified to ˜pH 9 with 2N HCl (6 mL). The cold mixture was filtered and washed with deionised water, yielding the title compound as a crude product. MS (ES) MH⁺: 292, 294 for C₁₁H₁₅Cl₂N₃O₂.

Intermediate 245

The following Intermediate was prepared by the procedure described in Intermediate 16 from the starting materials (SM) indicated.

Int Compound Data SM 245 ethyl 4-{[(1-methyl-1- phenylethyl)amino]carbonyl}- 2-(methylsulfonyl)-1,3- thiazole-5-carboxylate

MS (ES) MH⁺: 397 for C₁₇H₂₀N₂O₅S₂ NMR: 1.24-1.32 (m, 3H) 1.66 (s, 6H) 3.57 (s, 3H) 4.36 (q, 2H) 7.22 (t, 1H) 7.34 (t, 2H) 7.41-7.50 (m, 2H) 8.91 (s, 1H) Intermediate 246

Intermediate 246 ethyl 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylate

Diisopropylamine (5.3 ml) was dissolve in anhydrous THF (100 ml) was cooled to −78° C. and to this was added n-butyl lithium (15 ml) slowly. The solution was slowly warmed to 0° C. and then cooled back to −78° C. A solution of N-(1-methyl-1-phenylethyl)-2-(methylthio)-1,3-thiazole-4-carboxamide (Intermediate 13; 3.7 g) in anhydrous THF was added slowly maintaining the temperature below −70° C. After stirring for 30 min, a solution of ethyl cyano formate (2.5 ml) in anhydrous THF was added in one portion and the reaction was stirred at −78° C. for 30 min followed by slow warming to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (×3), dried with MgSO₄ and concentrated to a black oil (0.84 g) NMR: 1.22-1.29 (m, 3 H) 1.63 (s, 6 H) 2.76 (s, 3 H) 4.28 (q, 2 H) 7.20 (t, 1 H) 7.32 (t, 2 H) 7.46 (d, 2 H) 8.75 (s, 1 H).

Intermediate 247 diethyl 2-chloro-1,3-thiazole-4,5-dicarboxylate

To a solution of tert-butyl nitrite (3.4 mL, 28 mmol) and copper (II) chloride (3.7 g, 28 mmol) in acetonitrile (50 mL) was added diethyl 2-amino-1,3-thiazole -4,5-dicarboxylate (4.6 g, 19 mmol, Intermediate 248) all in one portion. Gas evolution was observed. After 45 min of stirring at room temperature LCMS indicated complete product formation. After concentrating to remove acetonitrile the residue was partitioned with chloroform and 1N HCl (Fisher), washed with chloroform, dried with MgSO₄ and concentrated to an orange oil. Purification by flash column yielded a pale yellow oil (4.2 g, 85%). MS (ES): 264; NMR: 1.25-1.29 (t, 3 H) 1.29-1.33 (t, 3 H) 4.28-4.33 (q, 2 H) 4.33-4.39 (q, 2 H).

Intermediate 248 diethyl 2-amino-1,3-thiazole-4,5-dicarboxylate

A solution of thiourea (1.7 g, 22 mmol) and diethyl 2-chloro-3-oxosuccinate (5.0 g, 22 mmol) in absolute ethanol (50 mL) was heated at reflux for one hour. After cooling to room temperature the solvent was removed leaving a white solid. The solid was dissolved in water (100 mL) and the resulting precipitate was filtered and dried (4.6 g, 87%). MS (ES): 245;

NMR: 1.21 (t, 3 H) 1.26 (t, 3 H) 4.16 (q, 2 H) 4.26 (q, 2 H) 8.04 (s, 2 H).

Intermediate 249 isopropyl 4-chloro-6-(morpholin-4-ylcarbonyl)pyridine-2-carboxylate

n-butyllithium (1.92 mL, 2.5M in hexanes) was added dropwise to a −78° C. solution of morpholine (0.42 mL, 4.8 mmol) in anhydrous THF followed by slow warming to room temperature. The solution was transferred to an addition funnel via cannulation and then added dropwise to a solution of dimethyl 4-chloropyridine-2,6-dicarboxylate (1.0 g, 4.4 mmol, Intermediate 251) in anhydrous THF. A slight precipitate was observed during the addition. After stirring two hrs at room temperature an additional 0.5 equivalence of the morpholino-lithium reagent was added to the reaction and after an additional two hrs of stirring another 0.5 equivalence was added followed by stirring one hour to reach completion. The solvent was removed under reduced pressure and the residue was suspended in methylene chloride and the product was extracted with a sat. sodium bicarbonate solution (×3). The sodium bicarbonate portion was acidified with conc. HCl to pH 3 and then extracted with EtOAc (×10), followed by drying with MgSO₄ and concentrating to a solid (0.8 g, 70%). MS (ES) MH⁺: 271 for C₁₁H₁₁ClN₂O₄. The solid was suspended in anhydrous toluene (75 mL) and to this was added triisopropylorthoformate (1.97 mL, 8.9 mmol) slowly followed by heating to reflux for 12 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was suspended in 1N HCl. Basification to pH8 with saturated sodium bicarbonate followed by extraction with EtOAc (×3), drying with MgSO₄ and removal of solvent yielded a tan solid. Purification by silica gel flash column (gradient elution to 3:1 EtOAc:CH₂Cl₂) yielded a white solid (0.23 g) MS (ES) MH⁺: 313 for C₁₄H₁₇ClN₂O₄; NMR: 1.33 (s, 3 H) 1.35 (s, 3 H) 3.41 (s, 2 H) 3.44 (d, 2 H) 3.58 (d, 2 H) 3.68 (s, 4 H) 5.17 (dt, 1 H) 8.01 (d, 1H) 8.13 (d, 1 H).

Intermediate 250

The following Intermediate was prepared by the procedure described in Intermediate 249 from the starting materials (SM) indicated.

Int Compound Data SM 250 isopropyl 4-chloro-6- [(dimethylamino)carbonyl] pyridine-2-carboxylate

MS (ES) MH⁺: 271 for C₁₂H₁₅ClN₂O₃ NMR: 1.35 (d, 6H) 2.93 (s, 3H) 3.03 (s, 3H) 5.18 (dt, 1H) 7.96 (d, 1H) 8.11 (d, 1H) Intermediate 251 and dimethylamine

Intermediate 251 dimethyl 4-chloropyridine-2,6-dicarboxylate

Phosphorus pentachloride (45.5 g, 218 mmol) was weighed into a closed flask and suspended in chloroform. 4-hydroxypyridine-2,6-dicarboxylic acid (10.0 g, 55 mmol) was added and after heating at a gentle reflux for 3 days the reaction was complete (60% conversion). After cooling to 0° C. anhydrous methanol (150 mL) was added dropwise. Once the exotherm subsided the solvent was removed under reduced pressure and the residue was partitioned with EtOAc and water and the insoluble material was filtered, washed with EtOAc and dried (6.7 g). The EtOAc layer was washed with water, dried with MgSO₄ and concentrated. Recrystallization with methanol yielded additional pure product (0.64 g). MS (ES) MH⁺: 230 for C₉H₈ClNO₄; NMR: 3.94 (s, 3 H) 8.32 (s, 1 H).

Intermediate 252 2-chloro-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid

To a solution of ethyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (2.5 g, 11 mmol, Intermediate 215) in acetone at 0° C. was slowly added a solution of chromium trioxide (2.26 g, 22 mmol) in 20% conc. Sulfuric acid in water (20 mL). After stirring at room temperature for 2 hrs, isopropanol (1 mL) was added to quench unreacted chromium trioxide. The reaction was diluted with water and the acetone was removed. Partitioning with methylene chloride (×3), drying with MgSO4 and concentrating yielded a white solid (2.3 g, 90%). MS (ES) MH⁺: 236 for C₇H₆ClNO₄S; NMR: 1.26 (t, 3 H) 4.31 (q, 2 H) 13.99-14.15 (m, 1 H).

Intermediate 253 3,4-Dichloro-5-chloromethyl-1H-pyrrole-2-carboxylic acid ethyl ester

To a 4-neck 22 L round bottom flask equipped with an overhead stirrer, liquid addition funnel, nitrogen inlet and an internal temperature probe was charged (Intermediate 254, 2000 g, 13.6 mol) and carbon tetrachloride (12 L). The reaction mixture was cooled to −5° C. and sulfuryl chloride was added at a rate that the temperature did not exceed 0° C. (1 h). Resulting reaction mixture became very thick (as precipitate becomes heavy, significant gas evolution was observed) and was allowed to stir at 0° C. for a total of 4 h after addition. Precipitate was filtered and solid azeotroped with toluene to remove excess sulfuryl chloride. The solid was and dried in convection oven at 50° C. yielding 3 (2077 g, 62%) as a dark purple solid.

Intermediate 254 5-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester

To a 4-neck 22 L round bottom flask equipped with an overhead stirrer, liquid addition funnel, nitrogen inlet and an internal temperature probe was charged ethyl 3-oxobutanoate (1952 g, 15.0 mol) and glacial acetic acid (5 L). The resulting solution was cooled to 0° C. with an ice water bath and an aqueous solution of sodium nitrite (1242 g, 18.0 mol, 1.2 eq, in 1875 ml of water) was added slowly (4.5 h) not allowing the internal temperature above 10° C. The homogeneous red solution was allowed to warm to ambient and stirred for 48 h. The solution color changed from light red to yellow. Reaction vessel was then placed in a heating mantle, fitted with a reflux condenser and acetylacetaldehyde dimethyl acetal (1982 g, 15.0 mol, 1 eq) was added in one portion (the top of the reflux condenser was left open to air to allow for the rapid gas evolution during the addition of the zinc). Zinc (dust, 2156 g, 33 mol, 2.2 eq) was added in portions (at a rate such that gas evolution was controlled) over 4 h. The addition of zinc brought the reaction to reflux and after addition the dark red solution was heated at reflux for an additional 1.5 h. Contents of the reaction were poured hot into a 50 L container with 20 kg of ice and allowed to stir for 16 h. Resulting suspension was filtered, dried in convection oven and recrystallized with hot heptane yielding a light yellow solid (312 g, 13.6% yield).

Intermediate 255 ethyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate

To a stirred solution of potassium hydroxide (42 g, 752 mmol) in dry methanol (100 mL), at 0° C. and under an atmosphere of N₂, was added a solution of ethyl 4-oxopiperidine-1-carboxylate (26.4 mL, 29.96 g, 175 mmol) in dry methanol (75 mL) via syringe. The resulting solution was stirred for an additional 30 minutes under an atmosphere of N₂ at 0° C. To it, in small portions over approximately 90 minutes, was added iodobenzene diacetate (84.6 g, 262 mmol). Temperature was kept near 0° C. throughout this time. The reaction was stirred overnight under an atmosphere of N₂, gradually reaching room temperature. Complete conversion was suggested by TLC (50% ethyl acetate in hexanes; Hanessian's stain; Rf˜0.25) in the morning. The reaction was concentrated under vacuum. To the residue was added approximately 50 mL water; from this mixture was extracted the crude product with ethyl acetate (3×200 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated. The crude product was purified using column chromatography (silica gel; 10-65% ethyl acetate in hexanes), yielding 26.74 g (66%) of a pale yellow oil.

MS (ESI) M: 233 for C₁₀H₁₉NO₅. ¹H NMR (CDCl₃): 1.22 (t, 3H), 1.69-1.86 (m, 2H), 2.20 (m, 2H), 2.86 (t, 1H), 3.22 (s, 3H), 3.23 (s, 3H), 3.74 (m, 1H), 3.95 (m, 2H), 4.11 (q, 2H).

Intermediates 256-257

The following Intermediates were synthesized by an analogous method to Intermediate 28 or Intermediate 59 from the starting materials (SM) given in the table below.

Int Compound Data SM 256 Cis(±)-ethyl 4-amino-3- MS (ESP): 227 (M + H) Intermediate (prop-2-yn-1- for C₁₁H₁₈N₂O₃ 146 yloxy)piperidine-1- carboxylate 257 Cis(±)-Ethyl (4-amino-3- MS (ES) MH⁺: 217 for Intermediate ethoxypiperidine-1- C₁₀H₂₀N₂O₃ 156 carboxylate

Intermediates 258-259

The following Intermediates were synthesized by an analogous method to Intermediate 37 or Intermediate 83 from the starting materials (SM) given in the table below.

Int Compound Data SM 258 tert-Butyl (3S,4R)-4-{[(4-chloro-5-methyl-1H- MS (ES) MH⁺: 360 Intermediate pyrrol-2-yl)carbonyl]amino}-3- for C₁₆H₂₃ClFN₃O₃; 64 and fluoropiperidine-1-carboxylate Intermediate 6 259 tert-butyl (3S,4R)-4-{[(4-chloro-3-fluoro-5- MS (ESP): Intermediate methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}- 530 (MNa⁺) for 263 and 1H-pyrrol-2-yl)carbonyl]amino}-3- C₂₂H₃₆ClF₂N₃O₄Si Intermediate fluoropiperidine-1-carboxylate 64

Intermediates 260-261

The following Intermediates were synthesized by an analogous method to Intermediate 50 or Intermediate 74 from the starting materials (SM) given in the table below.

Int Compound Data SM 260 4-Chloro-N-[(3S,4R)-3-fluoropiperidin-4- yl]-5-methyl-1H-pyrrole-2-carboxamide

MS (ES): MH⁺: 260 for C₁₁H₁₅ClFN₃O Intermediate 258 261 4-chloro-3-fluoro-N-[(3S,4R)-3- MS (ESP): 278 Intermediate 262 fluoropiperidin-4-yl]-5-methyl-1H-pyrrole- (MH⁺) for 2-carboxamide C₁₁H₁₄ClF₂N₃O

Intermediate 262 tert-butyl (3S,4R)-4-{[(4-chloro-3-fluoro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate

tert-butyl (3S,4R)-4-{[(4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate (Intermediate 259, 80 mg, 0.16 mmol) was dissolved in anhydrous THF (6 ml), followed by the addition of tetra-butyl ammonium fluoride (1 ml, 1M in THF) and ethylene diamine (1 mmol), the mixture was then stirred at 50° C. over night. After cooling down to room temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (100%˜70% hexanes/ethyl acetate) to give the desired product (55 mg).

MS (ESP): 378 (MNa⁺) for C₁₆H₂₂ClF₂N₃O₃.

¹H-NMR (CDCl₃) δ: 1.46 (s, 9H); 1.84 (m, 2H); 2.24 (s, 3H); 2.89 (m, 2H); 4.28 (m, 2H); 4.50 (m, 1H); 4.70 (m, br, 1H); 6.32 (m, 1H); 9.36 (br, 1H).

Intermediate 263 4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylic acid

tert-butyl 4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 264, 100 mg) was dissolved in N-methylpyrrolidinone (10 ml), heated to 200° C. for 30 minutes. The resulting solution was carried on to the next step without further purification.

MS (ESP): 307 (M⁻) for C₁₂H₁₉ClFNO₃Si.

Intermediate 264 tert-butyl 4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate

tert-butyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 265, 480 mg, 1.13 mmol) was dissolved in dry THF (8 ml), cooled down to −78° C., n-BuLi (2.5M in Hexane, 3.39 mmol) was added dropwise into the mixture via syringe and the mixture was stirred at −78° C. for 30 min followed by a quick addition of N-Fluorobenzensulfonimide (1.25 g, 3.96 mmol in 5 ml of THF/Toluene 1:1), the resulting mixture was then stirred at −78° C. for 30 min and slowly warmed up to room temperature during a period of 12 hrs. The reaction was quenched at 0° C. with drops of saturated NH₄Cl solution and further diluted with EtOAc (50 ml). The organic phase was washed with brine and dried over anhydrous MgSO₄, concentrated to an oil and purified by flash column chromatography eluted with 10% EtOAc in Hexanses. The desired product was obtained as an oil (125 mg).

MS (ESP): 364 (MH⁺) for C₁₆H₂₇ClFNO₃Si.

¹H-NMR (CDCl₃) δ: 0.00 (s, 9H); 0.90 (t, 2H); 1.58 (s, 9H); 2.31 (s, 3H); 3.52 (t, 2H); 5.70 (s, 2H).

¹⁹F-NMR (CDCl₃) δ: −148.85.

Intermediate 265 tert-butyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate

Ethyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 266, 564 mg, 1.42 mmol), t-Butylacetate (330 mg, 2.84 mmol) and potassium t-butoxide (0.14 mmol) were mixed together and stirred at room temperature for 10 minutes, concentrated to an oil under vacuum. t-Butylacetate (330 mg, 2.84 mmol) and potassium t-butoxide (0.14 mmol) were added again into the reaction mixture, repeated the same procedure again. The resulting reaction crude was filtered through a short pass silica gel, washed with ethyl acetate, the combined filtrate was concentrated to an oil and purified by column chromatography (2% ethyl acetate in hexanses) to give the desired product as an oil (485 mg).

¹H-NMR (CDCl₃) δ: 0.00 (s, 9H); 0.90 (t, 2H); 1.58 (s, 9H); 2.33 (s, 3H); 3.52 (t, 2H); 5.75 (s, 2H).

Intermediate 266 Ethyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate

To a suspension of sodium hydride (76 mg, 3.16 mmol) in dry DMF (5 ml), solution of ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 267, 420 mg, 1.58 mg) was added, the resulting mixture was stirred at 0° C. for 30 minutes until gas evolution seized. Trimethylsilyl-ethylmethyl chloride (315 mg, 1.89 mmol) was added drop wise and stirred over night while allowing the reaction mixture warmed up to room temperature slowly. The reaction was quenched with cold water, diluted with ether (20 ml), washed with water and brine, the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (95% hexanes in ethyl acetate) to give the desired product as an oil (624 mg).

MS (ESP): 397 (MH⁺) for C₁₄H₂₃BrClNO₃Si.

¹H-NMR (CDCl₃) δ: 0.00 (s, 9H); 0.90 (t, 2H); 1.43 (t, 3H); 2.38 (s, 3H); 3.55 (t, 2H); 4.34 (q, 2H); 5.75 (s, 2H).

Intermediate 267 Ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate

Ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7, 300 mg, 1.6 mmol) was dissolved in dry dichloromethane (10 ml), N-bromosuccinimide (285 mg, 1.6 mmol) was added at 0° C. and resulting mixture was stirred at room temperature over night. The mixture was poured into cold sodium hydroxide aqueous solution (2M) (20 ml), extracted with diethyl ether (2×20 ml). The organic phase was then washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (hexanes/ethyl acetate, gradient) to give the desired product as a yellowish solid. (424 mg).

MS (ESP): 266 (MH⁺) for C₈H₉BrClNO₂.

¹H-NMR (CDCl₃) δ: 1.39 (t, 3H); 2.32 (s, 3H); 4.34 (q, 2H); 9.04 (s, br, 1H).

Intermediate 268 Trans(±)-tert-butyl-4-[(diphenylmethylene)amino]-3-hydroxypiperidine-1-carboxylate

tert-butyl-4-amino-3-hydroxypiperidine-1-carboxylate (11.9 g; 55 mmol) and benzophenone imine (10 g; 59 mmol; 1.05 eq.) were dissolved in anhydrous toluene and heated to reflux for 18 hrs. Monitored the reaction by TLC (30% EtOAc/hexanes with 0.1% triethylamine). The crude reaction was concentrated and purified by flash column chromatography. Isolation gave 18.4 g of the title compound in an 86% yield. LC/MS (ES⁺)[(M+H)⁺]: 381 for C₂₃H₂₈N₂O₃.

Intermediate 269 Cis(±)-tert-butyl-3-azido-4-[(diphenylmethylene)amino]piperidine-1-carboxylate

In a flame-dried flask triphenylphosphine (3.86 g; 14.7 mmol; 2 eq.) was dissolved in anhydrous THF (15 ml) and cooled to 0 C. DIAD (2.97 g; 14.7 mmol; 2 eq.) was slowly added dropwise. Upon addition a white precipitate formed. A THF solution containing tert-butyl-4-[(diphenylmethylene)amino]-3-hydroxypiperidine-1-carboxylate (Intermediate 268, 2.8 g; 7.36 mmol) was added (amount of THF added was such that the final concentration of alcohol was ca. 0.5-1M). The resultant reaction slurry was stirred at 0 C for 30 minutes. (PhO)₂PON₃ (4.05 g; 14.7 mmol; 2 eq.) was then added and the reaction was allowed to warm to RT and stirred for 12 hrs. Monitored by LC/MS. The reaction was concentrated and purified by flash column chromatography (0-30% EtOAc/hexanes with 0.1% triethylamine). Isolation gave 2.13 g of the title compound in 71% yield. LC/MS (ES⁺)[(M+H)⁺]: 406 for C₂₃H₂₇N₅O₂.

Intermediate 270 Cis(±)tert-butyl-4-amino-3-azidopiperidine-1-carboxylate

tert-butyl-3-azido-4-[(diphenylmethylene)amino]piperidine-1-carboxylate (Intermediate 269, 1.36 g; 3.3 mmol) was dissolved in 10 ml's of aqueous THF (5% H₂O). PPTS (850 mg; 3.4 mmol; 1.03 eq.) was added in a single portion. The initial cloudy solution became clear within minutes. Upon completion (as determined by LC/MS analysis) the reaction was concentrated and azeotropically dried with acetonitrile. No further purification. (LC/MS: see disappearance of starting material and formation of Ph₂C═O. Product is not observable due to lack of chromophore).

Intermediate 271 Cis(±)tert-butyl-3-azido-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate

Crude tert-butyl-4-amino-3-azidopiperidine-1-carboxylate (Intermediate 270, 3.3 mmol) was dissolved in anhydrous CH₂Cl₂ (10 ml) and DIEA (1.27 g; 1.6 ml; 9.9 mmol; 3 eq.). The solution was cooled to 0 C and 3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl chloride (736 mg; 3.5 mmol; 1.05 eq.) was added. The reaction was complete within 30 minutes. Dilute with CH₂Cl₂ and wash with H₂O (×2), brine and dried over Na₂SO₄. Filter and concentrate. Purify by flash column chromatography (0-60% EtOAc/hexanes). Isolation gave 967 mg in 69% yield over the two-step sequence. LC/MS (ES⁻)[(M−H)⁺]: 415, 417 for C₁₆H₂₂Cl₂N₆O₃.

Intermediate 272 Cis(±)N-(-3-azidopiperidin-4-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide hydrochloride

tert-butyl-3-azido-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 271, 967 mg; 2.3 mmol) was dissolved in 4N HCl in dioxanes (20 ml) and methanol (10 ml). The solution was stirred for 2 hours and monitored by LC/MS. Upon completion the solvent was removed and the crude reaction mixture was azeotroped with methanol to remove excess HCl. No further purification. LC/MS (ES⁺)[(M+H)⁺]: 317, 319 for C₁₁H₁₄Cl₂N₆O.

Intermediate 273 (2R)-2-Methoxypropan-1-amine hydrochloride (1725-162)

tert-Butyl [(2R)-2-methoxypropyl]carbamate (Intermediate 277, 0.33 g, 1.74 mmol) and Hydrochloric acid (4 M, 1.5 mL) were combined and stirred at room temperature for two hours. Then it was concentrated and triturated with diethyl ether to give white crystalline solid (0.20 g) as the product.

NMR: 1.14 (d, 3H), 3.30 (s, 3H), 3.35-3.45 (m, 2H), 7.99 (brs, 3H).

Intermediates 274-275

The following compounds were produced according to the procedure for Intermediate 273 or by hydrogenation using the starting materials listed.

Int Compound Data SM 274 (2S)-2- NMR: 1.14 (d, 3H), 3.30 Intermediate methoxypropan-1- (s, 3H), 3.35-3.45 (m, 2H), 278 amine hydrochloride 7.99 (brs, 3H) 275 (2R)-1- NMR: 1.14 (d, 3H), 3.29 Intermediate Methoxypropan-2- (s, 3H), 8.07 (brs, 3H), rest of 276 amine hydrochloride the peaks are buried under huge water peak

Intermediate 276 Benzyl [(1R)-2-methoxy-1-methylethyl]carbamate

To a solution of benzyl [(1R)-2-hydroxy-1-methylethyl]carbamate (0.5 g, 2.38 mmol) in acetonitrile (20 mL), silver oxide (3.8 g, 13.09 mmol) is added followed by the addition of methyl iodide (1.94 mL, 23.8 mmol). The resultant mixture was stirred overnight at room temperature. The insoluble salt was filtered off and the filtrate was concentrated. The residue was flashed using silica and Ethyl acetate/hexanes system as eluent to give the desired product as clear oil (0.38 g).

MS (ES) MH+Na: 246 for C₁₂H₁₇NO₃;

NMR: 1.01 (d, 3H), 3.12-3.17 (m, 1H), 3.22 (s, 3H), 3.25-3.26 (m, 1H), 3.60-3.75 (m, 1H), 5.00 (s, 2H), 7.16 (d, 1H), 7.29-7.36 (m, 5H).

Intermediate 277 tert-Butyl [(2R)-2-methoxypropyl]carbamate

To a solution of tert-butyl [(2R)-2-hydroxypropyl]carbamate (0.4 g, 2.28 mmol) in THF (5 mL), sodium hydride (0.06 g, 2.51 mmol) was added at 0° C. The resulting solution was stirred for 30 minutes at that temperature and then methyl iodide (0.14 mL, 2.28 mmol) was added. The reaction was warmed to room temperature slowly and allowed to stir for an additional two hours. The reaction was quenched by adding water and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution, water and brine. It was dried over magnesium sulfate and concentrated. The desired product was obtained as clear oil (0.31 g) and it did not need any further purification.

NMR (CDCl₃): 1.15 (d, 3H), 1.43 (s, 9H), 3.31-3.33 (m, 2H), 3.34 (s, 3H), 3.77-3.81 (m, 1H), 4.66 (brs, 1H).

Intermediate 278 tert-Butyl [(2S)-2-methoxypropyl]carbamate

The title compound was synthesized by using the method analogous to the synthesis of Intermediate 277 starting with tert-butyl [(2S)-2-hydroxypropyl]carbamate and alkylating it with methyl iodide.

NMR (CDCl₃): 1.15 (d, 3H), 1.43 (s, 9H), 3.31-3.33 (m, 2H), 3.34 (s, 3H), 3.77-3.81 (m, 1H), 4.66 (brs, 1H).

Example 441

The following Example was prepared by the procedure described in Example 203 from the starting materials (SM) indicated.

Ex Compound Data SM 441 ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5- MS (ES) Example 188 and [2- methyl-1H-pyrrol-2- MH⁺: 605 for methoxy-1- yl)carbonyl]amino}-3- C₂₄H₃₃Cl₂N₅O₇S; (methoxymethyl)ethyl]amine methoxypiperidin-1-yl)-4-({[2- (ChemPacific) methoxy-1- (methoxymethyl)ethyl]amino}carbonyl)- 1,3-thiazole-5-carboxylate

Example 442

The following Example was prepared by the procedure described in Example 383 from the starting materials (SM) indicated.

Ex Compound Data SM 442 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H- pyrrol-2-yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-({[2-methoxy-1- (methoxymethyl)ethyl]amino}carbonyl)-1,3- thiazole-5-carboxylic acid

MS (ES) MH⁺: 578 for C₂₂H₂₉Cl₂N₅O₇S NMR: 1.77 (s, 2H) 2.19 (s, 3H) 3.24 (s, 3H) 3.27 (s, 3H) 3.38 (s, 5H) 3.49 (s, 6H) 4.32 (s, 2H) 7.18 (s, 1H) 8.93 (s, 1H) 12.16 (s, 1H) 16.17 (s, 1H) Example 441

Example 443

The following Example was prepared by the procedure described in Example 417 from the starting materials (SM) indicated

Ex Compound Data SM 443 sodium 2-((3S,4R)-4-{[(3,4- dichloro-5-methyl-1H-pyrrol-2- yl)carbonyl]amino}-3- methoxypiperidin-1-yl)-4-({[2- methoxy-1- (methoxymethyl)ethyl]amino}car- bonyl)-1,3-thiazole-5-carboxylate

MS (ES) MH⁺: 578 for C₂₂H₂₈Cl₂N₅O₇SNa NMR: 1.70 (s, 2H) 2.17 (s, 3H) 3.21-3.26 (m, 6H) 3.34 (s, 4H) 3.35-3.38 (m, 6H) 3.49 (s, 1H) 3.86 (d, 1H) 4.04-4.16 (m, 3H) 4.22 (s, 1H) 7.18 (d, 1H) 12.17 (s, 1H) 13.33 (d, 1H) Example 442 

1. A compound:

and/or a pharmaceutically acceptable salt thereof.
 2. A compound:

and/or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 2, in the form of a free acid.
 4. The compound of claim 2, in the form of a mixture of a free acid and a pharmaceutically acceptable salt thereof.
 5. The compound of claim 2, in the form of a pharmaceutically acceptable salt.
 6. The compound of claim 5, in the form of a potassium salt.
 7. The compound of claim 5, in the form of a sodium salt.
 8. A pharmaceutical composition comprising a compound of claim 2, and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or carrier.
 9. The pharmaceutical composition of claim 8, wherein the compound is in the form of a potassium salt. 